N-(1-acyl-3-indolyl)-acids



United States Patent 3,275,645 N-(1-ACYL-3-INDOLYL)-ACIDS Tsung-Ying Sheri, Westfield, N..l., assignor to Merck &

(30., Inc, Rahway, NJ, a corporation of New Jersey No Drawing. Filed Nov. 6, 1963, Ser. No. 321,686 20 Claims. (Cl. 26tl-304) This application is a divisional continuation-in-part of my copending application, Serial No. 164,615, filed January 5, 1962, and now abandoned, which was a continuahon-impart of my application Serial No. 97,434, filed March 22, 1961, and now abandoned.

This invention relates to new chemical compounds. More particularly, it relates to a new class of compounds of the indcle series. Still more particularly, it is concerned with new a-(3-indolyl)-lower aliphatic acids having a benzisoxazole, benzimidaaole, benzofuran, benzlothiazole, benzotriazole, benzoxazole, benzothi-ophene, indole, indazole or isindazole carboxylic acyl radical attached to the nitrogen atom of the indo-le ring. It is concerned further with salts, esters and amide derivatives of such compounds. It relates also to the synthesis of such substances.

The new aroyl and hetercaroyl indolyl aliphatic acid compounds of this invention have the general structural formula:

l a R H:CHCOM N/ R2 R4 in which R may be a benzisoxazole, benzimidazole, benzofuran, benzothiazole, benzotriazole, benzoxazole, benzothiophene, indole, indazole or isindazole, hereinafter referred to collectively as (benzo hetero aryl) or a substituted benzisoxazole, benzimidazole, benzofuran, benzothiazole, benzo triazole, benz-oxazole, benzothiop hene, indole, indazole or isindaziole radical in which the substituents may be halogen, lower alkyl, lower alkylthio, lower allcoxy, lower alkanoyl, cyano, carb lower alkoxy, carbamyl, lower alkyl sulfonyl, benzylthio, mercapto, nitro, amino, di (lower alkyl)amino, lower alkanoylamino, hydroxy, benzyloxy, dilower alkanoylamino, phenyl, lower allco-Xyphenyl, benzoyl, lower alkylamino, thenoyl, benzyl, dilower alkoxy loweralkyl, loweralkoxyl loweralkyl, morpholino loweralkyl or lower alkenyl;

R may be hydrogen, lower alkenyl or lower alkyl;

R may be hydrogen or lower alkyl;

R; may be hydrogen, lower alk-oxy, fluorine, lower alky or trifluoro-methyl;

R may be hydrogen, lower alkyl lower alkoXy, nitro, amino, di(lower alkyl) amino, lower lalkanroylamino, lower alkanoyl, bis(hydroxy lower alkyDamino, l-pyrrolidino, 4-methyl-1-piperizinyl, 4-mo-rpholinyl, cyano, amino lower alkyl, di(lower alkyl) amino lower alkyl, triflu oromethyl, halogen, di(lower alkyl)sulfamyl, benzylthio, lower alkylbenzylthio, lower alk-oxy benzylthio, halogenobenzylthio, benzyloxy, lower alkylbenzyloxy, lower alkoxybenzyloxy, halogenobenzyloxy, lower alkenyl, lower alkenyl-oxy, l-azacyclopro-pyl, cyclopropylmethyloxy or eyclobutylmethyloxy;

3,275,545 Patented Sept. .27, 1966 'ice and M may be OH, NH lower *alkoxy, benzyloxy, OZ where Z is a cation or OY where Y is the structure:

In the most preferred compounds of the invention, R is a lower alkyl, lower allcoxy, nitro, amino, or substituted amino. Examples of the alkyl and alkoxys are methyl, ethyl, propyl, t-butyl, methoxy, ethoxy, .i-propoxy and the like. R is not limited to this class of substituents, however, and may, if desired, represent substituents such as hydrogen, aryl, aryloXy, hydroxy, mercapto, halo, pseudohalo such as CF CHF or other haloalkyls, nitro, amino, alkylamino, acylalmino, haloalkyl, cyano, sulfarnyl, sulfoxide, aminomethyl, substituted aminomethyl, carboxy, carboalkoxy groups.

A critical feature of the new compounds described herein is the presence of a benzo hetero aryl radical attached to the N-l position of the indole. These acyl groups may be further substituted in the aromatic ring with hydrocarbon groups or with functional substituents. Thus, suitable acyl substituents are the benzisoxazolecarbonyl, benzimidazole-carbonyl, benzofuran-carbonyl, benzothiaZole-carbonyl, benzotriazole-carbonyl, benzoxazole-carbonyl, benzothiophene-carbonyl, indiole-carbwonyl, indaziole-carbonyl and isindazole-carbonyl groups. The aromatic rings of such groups may contain at least one functional substituent. This substituent may be a hydroxy or an etherified hydroXy (hydrocarbonoxy) group such as a lower alkoxy, e.g., methoxy, ethoxy, .isopropoxy, propoxy, a dilower alkoxy loweralkyl, an alkenyloxy such as allyloxy, a lower alkoxy loweralky'l, or an aralkoxy group, e.g., benzyloxy and the like. It may be a nitro radical, a halogen such as chlorine, bromine, iodine or fluorine, an amino group or a substituted amino group, representative examples of which that might be mentioned are benzamido, lower alkylamino, lower dialkylamino and dilower alkanoylamino. Further, it may be a mercapto or a substituted mercapto radical of the type exemplified by alkylthio groups such as methylthio, ethylthio, and propylthio and aralkylthio groups, e.g., benzylthio. The N-l aroyl may be acyl-ated as with acetyl, propionyl, benzoyl, thenoyl, and like acyl groups. In addition, the invention embraces compounds wherein the aroyl radical contains a cyarro, phenyl, benzyl, lower alkenyl, or morpholino lower alkyl radical. Further, it may contain a lower alkyl ester of a carboxy radical and the like.

The a-(3-indolyl)-aliphatic acids described herein are preferably lower aliphatic acids such. as u-(3-indolyl) derivatives of acetic, propionic, butyric, valeric and like acids. Lower alkyl esters, salts and the amides of such aliphatic acids represents an additional aspect of the invention. The esters are important intermediates in the synthesis of the free acids, and in many cases are themselves of importance as end products. The preferred esters are the lower alkyl esters such as. the methyl, ethyl, propyl or t-butyl compounds and the benzyl, p-halobenzyl and like esters.

The salts of these new a-(Lbenzo hetero aroyl-3-indolyl)-l0wer aliphatic acids can be obtained by treatment of the free acid with base under mild conditions. In this manner there may be obtained alkaline metal salts such as the sodium and potassium, the aluminum or magnesium salts or salts of alkaline earth metals, examples of which are barium and calcium. Salts of organic amines such as dimethylamine, morphcline, methyl cyclohexylamine or glucosamine may be obtained by reacting the acid with the appropriate organic base. The amides included within this invention are conveniently synthesized by first preparing the amide of an a-(3-indolyl)-lower aliphatic acid unsubstituted at the 1-position and then acylating said compound by the process described hereinbelow. Such amides are conveniently obtained by reacting the free acid with urea or treating the appropriate acid chloride with ammonia.

The 2-position of the indole ring nucleus (R in the above formula) may be hydrogen although it is preferred that there be present at this position of the molecule a hydrocarbon radical having less than nine carbon atoms. Lower alkyl groups such as methyl, ethyl, propyl or butyl are the most satisfactory, but lower alkenyl radicals also can be used.

The following compounds are representative of those contemplated by this invention and which may be prepared by the procedure discussed hereinbelow:

methyl a-[ 1-coumar1oyl2-methyl-5 -methoXy-3- indolyl] -acetate,

methyl oc-[ 1-(5-nitrobenzoxazolyl carbonyl) picolinoyl- 2,5 -dimethyl-3-indolyl] -acetate,

methyl a-[1-(6-bromo-2-methylbenzimidazole-S-carboxy) -2-methyl-5-methoxy-3-indolyl] -acetate,

a-[ 1- (benzothiazolyl-Z-carb oxy) -2-methyl-5-methoxy- 3-indolyl]-propionic acid,

a- (benzisoxazol-Z-carboxy-2-methyl-5-methoxy-3 indolyl) -acetamide,

ozbenzofuran-3 -carboxy) 2-methyl-5-methoxy-3 indolyl) -acetamide,

et-hyl a[ 1(1-phenylisindazol-3-carboxy) -2-methyl-5- methoXy-3-indolyl] -propionate,

benzyl a-[ 1- (thionaphthene-2-carboxy) -2-methyl-5- methoxy-3-indoly1] -acetate, and the like.

The a-(l-benzo hetero aryl-S-indolyD-lower aliphatic acids and derivatives thereof described herein are synthesized by acylation of the a-(3-indO1yD-lOWer aliphatic acid, ester or amide having the desired substituents at the 2- and 5-positions of the ring nucleus. It is preferred to carry out the acylation on an ester or amide derivative of the lower aliphatic acid. In those cases where the free acid is desired, the ester may be converted under suitable reaction conditions to the free acid. It has been observed that the l-acyl substituent is easily hydrolyzed under conditions normally employed for saponification of an ester to the free acid. For this reason, care must be taken in converting the a-(lacyl-3-indolyl)-lower aliphatic acid esters to the corresponding free acids. It has been found that one convenient method of accomplishing this conversion comprises acylation of the benzyl ester and subsequent hydrogenolytic removal of the benzyl ester. Alternatively, other esters such as the t-buty'l esters, which are amenable to selective removal by other treatment, such as heating above 210 C. or by heating at 25- l C. in the presence of a catalytic amount of an aryl sulfonic acid or other acids, may be utilized. When, instead of an ester, the amides of these acids are prepared, the free acids are formed by reaction of the amides with a stoichiometric quantity of nitrous acid in an inert solvent.

The acylation reaction is conducted by one of two methods. One such consists of treating the u-(3-indolyl)- lower aliphatic acid starting material with an alkali metal hydride such as sodium hydride to form e.g., a sodium salt and then intimately contacting said salt with the benzo hetero aryl carboxylic acid halide in an anhydrous solvent medium. It is preferred to employ solvents such as dim-ethylformamide, dimethylformamide-benzene, benzene, toluene or xylene. It is preferred to carry out the acylation of about room temperature although lower temperatures may be employed if the particular reactants are unduly susceptible to decomposition.

An alternative (and when using the basic benzo hetero aroyl acids, greatly preferred) method of acylating the 1- position is by use of a phenolic ester of the acyla-ting acid, such as the p-nitrophenyl ester. This latter is prepared by mixing the acid and p-nitrophenol in tetrahydrofuran and adding dicyclohexyl carbodiimide in tetrahydrofurane slowly. The dicyclohexylurea which forms is removed by filtration and the nitrophenylester is recovered from the filtrate. Alternatively, there can also be used the anhydride, azide or thiophenolic ester of the acylating acid. Whichever is used, the acyclation of the u-(3-in dolyl)-lower aliphatic acid starting material is achieved by forming a sodium salt of said material with sodium hydride in an anhydrous solvent and adding the nitrophenylester. Because of the basic character of these aroyl acids, this method is preferred over the acid chloride method for benzisoxazole, benzimidazole, benzothiazole, benzoxazole, indole indazole and isindazole carboxy indoles.

The a-(1-3-indolyl)-lower aliphatic acid compounds of this invention have a high degree of anti-inflammatory activity and are effective in the prevention and inhibition of granuloma tissue formation. Certain of them possess this activity in high degree and are of valve in the treatment of arthritic and dermatological disorders and in like conditions which are responsive to treatment with anti-inflammatory agents. In addition, the compounds of this invention have a useful degree of antipyretic activity. For these purposes, they are normally administered orally in tablets or capsules, the optimum dosage depending, of course, on the particular compound being used and the type and severity of infection being treated. Although the optimum quantities of these compounds of this invention to be used in such manner will depend on the compound employed and the particular type of disease condition treated, oral dose levels of preferred compounds in the range of 10 2000 mg. per day are useful in control of arthritic conditions, depending on the activity of the specific compound and the reaction sensitivity of the patient.

The indolyl aliphatic acid compounds employed as starting material in the reaction discussed above, and having the formula:

. R3 H(IIHOOE N Rr R4 I H where R R R and R have the previously defined meanings and E is a hydrocarbonoxy radical having less than nine carbon atoms or -NH may be synthesized in various ways. When R is hydrogen or methyl, it is preferred to form such compounds by reacting together an appropriately substituted phenylhydrazine and a substituted levulinic ester amide to form an intermediate phenylhydrazone which cyclizes under the reaction conditions to the indole compound where R R R and E are as above, and R is hydrogen or methyl. The reaction is normally carried out in a lower a'lkanol such as methanol, ethanol, isopropanol or butanol containing an acid such as hydrochloric, hydrobromic, sulfuric or acetic acid or in aqueuos mineral acid, such as concentrated hydrochloric, hydrobromic, sulfuric or acetic acid, or other Lewis acids such as ZnCl BF SnCl and the like. The acid serves as a catalyst in the condensation and ring closure reactions leading to the l-unsubstituted indole. When the substituted levulinic esters are used, the nature of the ester is not critical, although it is preferred to utilize a lower alkyl ester, e.g., the methyl, ethyl, propyl, .isobutyl or isopropyl compound. To avoid the possibility of transesterification the alcohol used as the solvent medium is preferably the same as the alcohol moiety of the ester. When R is hydrogen, it is convenient to employ the aldehyde in the form of an acetal, e.g., methyl 'y,'y-dimethoxy butyrate. An acid addition salt of the phenylhydrazine reactant, for example the hydrochloride, is normally preferred over the free base for practical reasons, although such salts and the base are equivalent in the reaction itself.

Formation of the oc-(3-indo1yl)-a-liphatic acid, or ester thereof, is brought about at elevated temperatures, good results being obtained by refluxing the reaction mixture for at least about 15 minutes. Longer reaction times are not harmful and may be used if desired. The desired compound is recovered from the reaction mixture and purified by techniques such as solvent extraction, chromatography and/or distillation. Since the l-unsubstituted esters are low melting solids, they are conveniently purified by distillation under reduced pressure. They are saponified by treatment with an alkali metal hydroxide.

The substituted phenylhydrazines employed as one of the starting materials in this synthesis are prepared by known methods. One convenient method is by diazotization of the appropriately substituted aniline to give the diazo compound, treatment of the latter with stannous chloride to form a tin complex, and decomposition of this complex to the phenylhydrazine with sodium hydroxide.

The l-acyl group in a( l-acyl-3-indolyl) aliphatic acids and esters of this invention are, as has been mentioned earlier, easily hydrolyzed under the conditions normally used to saponify an ester. For this reason, the benzyl ester of the intermediate a-(1-unsubstituted-3-indolyl) acids are a convenient starting material. These are obtained by forming the free a-(l-unsubstituted-3-indolyl) aliphatic acid and esterifying this with benzyl alcohol in an inert solvent with an acid catalyst (sulfuric, aryl sulfonic acids, e-tc.). Alternatively, the intermediate benzyl ester is synthesized directly by using the benzyl ester of the proper levulinic acid in the original synthesis of the indole ring, or is formed by base catalyzed ester exchange from other esters. After acylation of the indole nitrogen of these benzyl ester intermediates, the benzyl group can be removed clearly by hydrogenolysis, a process which leaves the l-acyl group untouched.

Alternatively, it is possible first to produce an indole of the formula:

\N/R2 R4 where R R and R have the same meaning as before, and then to introduce the carboxylic acid residue at the 3-position. This is accomplished by treating the indole of the above formula under Mannich reaction conditions with formaldehydedialkylamine to produce a substituted gramine, subsequently reacting this latter compound with an alkali metal cyanide in a lower alkanol, and finally hydrolyzing with a strong base such as sodium or potassium hydroxide.

While this method of introducing the aliphatic acid residue at the 3-position after elaboration of the indole ring is, of course, generally applicable to compounds having the structure shown above, it is particularly usfeul for making compounds of this invention wherein R is an alkyl radical other than methyl, such as the 2-ethyl, 2- propyl, 2-ally1 and like substances. Compounds of the above formula, unsubstituted in the 3-position, are readily prepared following the procedures set forth in columns 2 and 3 of US. Patent No. 2,825,734. Products where R is acyloxy, halo, cyano, carboxy, carbalkoxy, alkyl, aryl, aralkyl, nitro or hydrocarbonoxy are prepared via the synthesis beginning from a substituted 2-nitro-benzaldehyde or Z-nitrotoluene.

The synthesis of various compounds of this invention having on the indole ring system a 5-substituent which has a nitrogen attached to the homocyclic ring of the indole is generally based on the S-nitro compound. This is transformed into the desired S-substituent. Such transformation may be before or after acylation of the 1-position, depending on the extent to which the desired 5-substituent may interfere with the acylation. If such interference is possible, the 1-acylation should be carried out on the 5-nitro indole and the nitro later transformed into the desired S-substituent. Such transformation can be carried out in a number of ways. Reduction of the S-nitro groups gives a S-amino group. Reaction of the amino with alkyl halides gives mono and dialkyl amino groups. If the alkyl halide is a dihaloalkylene group (e.g., 1,4-dibromobutane) a heterocyclic ring (e.g., pyrrolidino) is formed. Similarly, bis (fi-chlorethynether will give an N-morpholino compound. Alkylation can also be carried out simultaneous with reduction, as e.g., with formaldehyde and Raney nickel and hydrogen. Acylation can similarly be carried out on the S-amino compounds or on the S-nitro (with simultaneous reduction) to give S-acylamid-o compounds. The S-amino group can be reacted with isocyanates to give S-ureido compounds.

A free mercapto, hydroxy or unsubstituted ring nitrogen group in the benzo hetero acyl compounds, will react under acylating conditions. Therefore, it is necessary to protect those groups prior to acylation. In those cases where the benzo hetero acyl compound con tains a free mercapto group, the synthesis of the final compound of the invention is as follows: (1) protection of the mercapto group on the benzo hetero acyl ester by reaction with methoxymethyl chloride, (2) saponification of the methoxymethyl acyl ester to the free acid, (3) formation of the pnitropheny-lester of the methoxymethyl-acyl acid, by reaction with p-nitro phenol, (4) acylation of the p-nitrophenyl acyl ester with the chosen indole compound, and (5) removal of the methoxymethyl group of the acylated indole compound, by hydrolyses of the acylated indole ester to produce the l-(mercapto substituted benzo hetero aroyl)-3-indolyl ester. When the benzo hetero acyl compound contains a hydroxy group, the synthesis of the final compound of this invention is as follows: (1) protection of the hydroxy group on the benzo hetero acid ester by reaction with benzyl chloride to produce the benzyloxy benzo hetero acid ester and saponification of the ester to the free acid, (2) formation of the p-nitrophenylester of this benzo hetero acid by reaction with p-nitrophenol, (3) acylation of the above p-nitrophenylest-er with the chosen indole compound to produce the l-(benzyloxy substituted benzo hetero aroyl)-3-indolyl ester, and (4) conversion of the benzyloxy group to the hydroxy group by reduction of the above compound to produce the l-(hydroxy substituted benzo hetero aroy1)-3-indolyl ester. In those cases Where the benzo hetero acyl compound contains an unsubstituted ring nitrogen such as in indole, indazole, iso-indazole, benzimidazole and the like, the synthesis of the compounds of this invention is identical to the above-mentioned synthesis, for the mercapto compound, except that it is the ring nitrogen which is protected. In addition, the above synthesis may be varied by replacing the methoxymethyl chloride protecting agent with benzyl chloride. Furthermore, in those cases 7 where the benz o hetero acyl compound contains a free hydroxy as well as an unsubstituted ring nitrogen the procedure used for the mercapto case is also employed.

EXAMPLE 1 A. Ethyl ot-(Z-methyl-S-methxy-3-ind0lyl)-pr0pi0nate A solution of 25 g. of p-methoxyphenylhydrozine hydrochloride and 20 g. of ethyl tic-methyl levulinate in 250 ml. of 2 N ethanolic hydrochloride is heated on a steam bath for a few minutes. An exothermic reaction takes place with the separation of ammonium chloride. The reaction flask is removed from the steam bath and the mixture allowed to reflux gently until the initial reaction subsides. The mixture is again heated on a steam bath under reflux for 30 minutes, and then concentrated in vacuo to a volume of about 80 ml. The concentrate is diluted with about 400 ml. of Water and extracted With ether. The resulting ethereal extract is washed with a saturated solution of sodium bicarbonate, and with water, and dried over anhydrous sodium sulfate. The dried solution is filtered and evaporated to a dark brown syrup which is purified by chromatography over about 1 lb. of acid-washed alumina in a 2%" ID. column using mixtures of ether and petroleum ether (v./v. 1:9 to 1:1) as eluen-t. The light yellow syrup so obtained is distilled in a short-path distillation apparatus and the product collected at 13.1. ISO-153 C. (0.25 mm.). The distillate of ethyl a-(2-methyl-5-methoxy-3-indolyl)-propionate crystallizes on triturati on with petroleum ether, M.P. 5355.5 C. On recrystallization from a mixture of ether and petroleum ether the melting point is unchanged.

Calcd. for C H O N: C, 68.94; H, 7.33; N, 5.36. Found: C, 69.23; H, 7.31; N, 5.60.

When the methyl, propyl, isopropyl or benzyl ester of ot-Inethyl levulinic acid is employed in the above reaction in place of the ethyl ester, there is obtained methyl or (2-methyl-5-methoxy-3-indolyl)-propionate, propyl OL- (2 methyl 5-methoxy-3-indolyl)-propionate, isopropyl tx-(2-methyl-5-methoxy-3inodolyl)-propionate, or benzyl ot-(2-methyl-5-methoxy-3-indo1yl)-propionate, respectively. Alternatively, when an ester of levulinic acid is used as starting material in the above process, the corresponding ester of u-(Z-methyl-S-methoxy-3-indolyl)-acetic acid is obtained.

B. Ethyl ot-(2,5-dimethyl-3ind0lyl)-pr0pi0nate g. of p-methylphenylhydrazine hydrochloride and 20 g. of ethyl a-methyl levulinate are added to 250 m1. of 2 N ethanolic hydrogen chloride and the mixture warmed until reaction sets in. After the initial exothermic reaction stops, the mixture is refluxed for about /2 hour and then concentrated in vacuo to about /3 volume. 400 ml. of water are added and the aqueous solution extracted with ether. The ether extracts are washed with sodium bicarbonate solution, and with water, then dried over sodium sulfate. The ether solution is concentrated to a small volume in vacuo and chromatographed over acidwashed alumina (1 1b. of alumina in a 2%" ID. colcmn). The material eluted with ether-petroleum ether (v./v. 9:1 to 1:1) is distilled in a short-path distillation apparatus. Ethyl oz (2,5-dimethyl-3-indolyl)-propionate distills at ISO-170 (bath temp.)/l mm. and crystallizes on trituration with petroleum ether, MP. 88- 88.5" C.

When a lower alkyl or benzyl levulinate is employed in place of ethyl a-methyl levulinate, lower alkyl or benzyl- (2,5-dirnethyl-3-indolyl)-acetate is produced.

EXAMPLE 2 Ethyl (X- (I-c0umaril0yI-Z-methyl-5-methoxy-3-indolyl) propionale A suspension of 2.3 g. (0.046 m.) of 50% sodium hydride-mineral oil in 250 ml. of dimethylformamide is stirred for 20 minutes under nitrogen with ice-cooling. Then 8.64 g. (0.035 m.) of ethyl a-(2-methyl-5-methoxy- 3-indolyl)-propionate is added and the mixture stirred for 20 minutes. A solution of 0.046 m. of coumariloyl chloride in 50 ml. of dimethylformarnide is added dropwise over a period of 30 minutes. The mixture is stirred in an icebath for 5 hours under nitrogen. It is then poured into a mixture of 500 ml. of ether, 5 ml. of acetic acid and 1 l. of iced water. The organic products are extracted with 3 x 300 ml. of ether. The ether solutions are combined and washed with a large quantity of water, and dried over sodium sulfate. The solution is fiiltered, evaporated to near dryness and the residue charged onto a 300 g. alumina column. The ethyl ot(lcoumariloyl-Z-methyl-5-methoxy-3-indolyl)-propionate is eluted with 1030% ether in petroleum ether. It is obtained on concentration of the eluates to dryness.

The coumariloyl chloride starting material is obtained by heating a mixture of 0.15 m. of cournarilic acid and 0.18 m. of thionyl chloride on a steam bath for 1 hour. About 20 ml. of benzene is then added and boiled 011?. The remaining solution is centrifuged and diluted with petroleum ether. On cooling, the acid chloride separates.

When methyl (2-rnethyl-5-methoxy-3-indolyl)-acetate is employed as the starting material in the above process, there is obtained methy1-(l-courrnariloyl-Z-methyl-5-methoxy-3 -indolyl) -acetate.

EXAMPLE 3 Methyl 1-(I-methyl-indole-Z-carbonyl) -2-methyl-5- me2h0xy-3-ind0lyl acetate A. p-NITROPHENYLd-METHYL-INDOLE-2- CARBOXYLATE In a 500 ml. round bottom flask (all equipment flame dried) is added 13.9 g. of p-nitrophenol and 17 g. 1- methyl-indole-2-carboxylic acid in 250 'ml. dry tetrahydrofuran. Through a dropping funnel is added over 30 minutes 20.6 g. of dicyclohexyloarbodiimide in ml. of dry tetrahydrofuran. The reaction is allowed to run overnight with stirring. The dicyclohexylurea which forms during the reaction is filtered. The filter cake is washed with dry tetrahydrofuran. The solution is evaporated to dryness. The solid is taken up in benzene and washed with sodium bicarbonate solution and then with water and dried over anhydrous sodium sulfate. The solution is concentrated under vacuum to dryness. The solid p-nitrophenylester is then recrystallized from benzene.

B. METHYL 1-(1\IETHYL-I.NDOLE-2-CARBO1NYL)-2- METHYL-fi-METHOXY-3-INDOLYLACETATE In a 250 ml. round bottom flask (flame dried equipment) is placed at 0 C. with nitrogen, 100 ml. of dry dimethylformamide with 10.5 g. of methyl ot-(2-iinethyl-5- methoxy-3-indolyl)-acetate. To this is added 2.5 g. of 50% sodium hydride mineral oil mixture. After the mixture is stirred for 30 minutes there is added over 15 minutes a solution of 15 g. of p-nitrophenyl l-methyl-indole- 2-carboxyl a'te in 50 ml. dry dimethylformamide. The reaction mixture is stirred for 4 hours at 0 C. under nitrogen followed by stirring under nitrogen at room temperature over night. The reaction mixture is then poured into an ice-water-ether solution containing a few ml. of acetic acid and the layers are separated. The aqueous phase is washed with ether and the ether extracts are combined and dried over sodium sulfate. To the ether solution is added a saturated solution of hydrogen chloride gas in dry ether. The ether is decanted ofl, leaving a heavy oil. The oil is washed with ether followed by an addition of aqueous sodium bicarbonate solution. The product is then extnacted with ether. The ether layer is dried over anhydrous sodium sulfate and concentrated to dryness. The product, methyl [1-(1-methyl-indole-2-carbonyl)-2- methyl-5-methoxy-3-indolyl]-acetate, is crystallized from benzene-Skellysolve B.

EXAMPLE 4 Methyl I-(coumariloyl)-2-methyl-5meth0xy-3-ind0lyl acetate The procedure of Example 3 is followed using coumarilic acid in place of 1 methyl-indole-Z-carboxylic acid in part A and the product thereof in the procedure of part B, to yield methyl l-(couim-ariloyl)-2-methyl-5-methoxy- 3-indolyl acetate.

Similarly, when S-acetamidobenzisoxazole-2-canboxylic acid, 5-ni trobenzisoxazole-Z-carboxylic acid, 5-chlorobenzisoxazole-Z-carboxylic acid, 5adiacetylaminobenzisoxazole2-carboxylic acid, 6-acetamido-5-bromobenzisoxaZole-3-oarboxylic acid, 6-acetamido-S-nitrobenzisoxazole-3-carboxylic acid, 6-nitrobenzisoxazole-3-carboxylic acid, 3-methyl-7-methoxybenzofuran carboxylic acid, 2benzoyl-6-methoxybenZofunan-3-carboxylic acid, 2-1nethyl-5-methoxybenzofuran-3-oarboxylic acid, 2-phenylbenzofuran-3-carboxylic acid, 2-acetyl-4-Inethoxybenzofuran-S-carboxylic acid, 4+methoxybenzofuran-S-carboxy]ic acid, 4-chlorobenzothiazole-Lcarboxylic acid, 6-nitrobenzothiazolea2-carboxylic acid, Z-actylthiobenzothiazole-S-carboxylic acid, 1-chlorobenzoithiazole-4-carboxylic acid, l-phenylbenzothiazole-4-carboxylic acid, Z-acetamidobenzothiazole-G-carboxylic acid, 2-(p-nitrophenyl) benzothiazole-6-oarboxy1ic acid, 1-rnethylbenzoxazole-4-carboxylic acid, 3-bromobenzothiophene-2-oarboxylic acid, Z-methylthianaphthene-S-carboxylic acid, 2 ethyl-2,3 dihydrothianaphthene-7-carboxylic acid, S-benzyloxy-Z-coumarilic acid, 5-dimethoxymethyl-Z-cotunarilic acid, 6-dimethylamino-3-'methyl-2-coumarilic acid, 3-ethoxyrnethyl-2-cournarilic acid,

S-fo rmyl-Z-cournarilic acid,

3-phenyl-2-couunarilic acid,

5-nitro-2-co-utmarilic acid, 4bromoindole-l-carboxylic acid, 1-benzylindole-2-carboxylic acid, 5-cy anoindole-l-carboxylic acid, 1-phenylindole-2-carboxylic acid, 6-nitroisindazolel-carboxylic acid, 1-methy1isindazole-3 -carboxylic acid, benzisoxazole -2-carboxylic acid, benzisoxazole-3-carboxylic acid, benzofurancarboxylic tacid, benzofuran-3-earboxylic acid, benzothiazole-2carboxylic acid, benzothiazole-6carboxylic acid, benzoxazole-S-carboxylic acid, thianaphthene-Z-carboxylic acid, thianaphthene-3-carboXylic acid, thianaphthene-6-carboxylic acid or indole- 1 -carboxylic acid are used instead of 1'methyl-indOle-Z-carboxylic acid in the procedure of Example 3, the corresponding methyl- 1-acyl2-methyl-5-methoxy-3-indolyl acetates are obtained.

EXAMPLE 5 Methyl [1- benzimidazole-Z-carb0nyl) -2methy 1-5- methoxy-3-indoyl] acetate A. ETHYL l-METH OXYMETHYLBENZIMIDAZOLE-Z- CARBOXYLATE To a solution of 0. 1 mole of ethyl benzimidazole-Z-carboxylate in 200 ml. of dimethylformamide is added with ice-cooling and stirring 0.12 mole of sodium hydride (50% emulsion in mineral oil) followed by 0.12 mole of methoxymethyl chloride in 20 ml. of dimethylform'amide. After 2 hours at 0 and 18 hours at room temperature,

the solution is poured into iced water and extracted with ether. The etheral solution is dried over sodium sulfate, filtered, concentrated and chromatographed on 300' g. of alumina using et her-petroleurn ether (v./v. 50-l00%) as eluent, to obtain ethyl-l-methoxymethylbenzimidazole-Z- carboxylate.

B. l-METHOXYMETHYLBENZIMIDAZOLE-2-CAR- BOXYLIC ACID The above ester is saponified by treating it with 1 N sodium hydroxide in aqueous ethanol at room temperature for 18 hours. This solution is then concentrated in vacuo, extracted with ether and carefully aciditied with dilute hydrochloric acid, with ice-cooling. The free acid is quickly taken into ether, washed with water, dried over sodium sulfate and evaporated, to yield essentially pure l-methoxymethylbenzimidazole-Z-carboxylic acid.

C. p-NITROPHENYL (l-METHOXYMETHYLBENZ- IMIDAZOLE-2-CARB OXYLATE) The procedure of Example 3A is followed using 1- methoxymethylbenzimidazole-Z-carboxylic acid in plac of l-methy-lindole-Z-carboxylic acid, to yield p-nitrophenyl l-methoxymethyl-benzimidazole-Z-carboxylate) D. METHYL [1-(1-METHOXYMETHYLBENZIMIDAZOLE- 2CARBONYL)2-METHYL 5 METHOXY-FJ-INDOLYL] ACETATE The procedure of Example 33 is followed using pnitrophenyl (l methoxymethylbenzimidazole-2-carboxylate) in place of p-nitrophenyl (l-methylindole-Z-carboxylate), to yield methyl [l-(-methox.ymethylbenzimidazole-Z-cahbonyl)-2-rnethyl-5-mehoxy-3-indoly1] acetate.

E. METHYL [1-(BENZIMIDAZOLE 2-CARBONYL)-2- METHYL-5-METHOXY-3-LNDOLYL] ACETATE The acylated indo'lyl acetic ester is dissolved in a solu-- tion of 0.1 N hydrochloric acid in 80% aqueous dioxan and allowed to stand at room temperature for 18 hours. This solution is then neutralized with dilute ammonium hydroxide, concentrated in vacuo, poured into water and extracted with chloroform. The chloroform solution is dried over sodium sulfate, evaporated and chromatographed on a column of alumina using ethyl-acetatebenzene (v./v. 1050%) as eluent, to yield methyl [1- benzimidazole 2 carbonyl) 2 methyl5-methoxy-3- indoyl] acetate.

When the ethyl esters of 5,6-dimethyl-benzimidazole-Z-carboxylic acid, 6-methoxy-Z-methyl-benzimidazole-4-ca'rboxylic acid, Z-phenylbenzimidazole--carboxylic acid, 6-bromo-2-methylbenzimidazole-S-carboxylic acid, 7 -acetamido-2-methylbenzimidazole-5-carboxy1ic acid, 2-methyl-7-nitrobenZimidaz0le-5-carboxylic acid, 7-acetamido-2-methylbenzimidazole-S-carboxylic acid, 6 bromoindole2-carboxylic acid, 6-fiuoroindole-2-car-boxylic acid, S-cyanoindole-Z-carboxylic acid, 3-ethyl4-fluoroindole-Z-carboxylic acid, 3-methoxyindole-Z-carboxylic acid, 3-Inorpholinomethylindole-Z-carboxylic acid, 7-nitroindole-2-carboxylic acid,

6-(1-pentenyl) indole-2-carboxylic acid, 5,7-dimethoxyindole-3-carboxylic acid, 2,3-dimethylindole-4-canboxylic acid, 7-methylindazole-Z-carboxylic acid, 2-methylindazole-3-carboxylic acid, benzimidazole-4-carboxylic acid, benzimid'azole-6-carboxylic acid, benzimidazole-S-carboxylic acid, benzimida-zoleJ-carboxy'lic acid, benzotriazole--carboxylic acid,

indole-3-carboxylic acid,

indole-4-carboxylic acid,

indole-S-carboxylic acid,

indole-6-carboxylic acid, indole-7-carboxylic acid, ind'azole-2-carboxylic acid or indazole-3-carboxylic acid are used insteal of ethyl benzimidazole-2-carboxylate in the above procedure, the corresponding methyl l-acyl-Z- methyl--methoxy-3-indolyl acetates are obtained. Similarly, when ethyl 5-hydroxy-Z merca-pto-benzimidazole-6- carboxylate (3 moles of 'methoxyrnethyl chloride), ethyl 2-methyl-5-hydroxybenzimid-azole-7-earboxylate (2 moles of methoxymethyl chloride), and ethyl 6-hydroxy-methylbenzimidazole-4-carboxylate are used in place of ethyl benzimidazole-2-canboxylate, in the above example, there are obtained methyl [l-(5-hydroxy-2-mercaptobenzimidazole-6- carbonyl)-2-methyl-5methoxy-3-indolyl] acetate,

methyl ['1-(2-methyl-5-hydroxybenzimidazole-7-carbonyl) -2-methyl-5-methoxy-3-in dolyl] and methyl [1-( 6-hydroxy-2-methylbenzimidazole-4- carbonyl)-2-methyl-5-methoxy-3-indolyl] acetate,

respectively.

EXAMPLE 6 [1-(benz0furan-4-carb0nyl) -2-methyl-5-methoxy-3- indolyl-acetic] acid A. 2-METHYL-5-METHOXYii-LNDOLYLACETIC ANHYDRIDE 'Dicyclohexylcarbodiimide (10 g., 0.049 mole) is dissolved in a solution of Z-methyI-S-methoxy-3-indolylacetic acid (22 g., 0.10 mole) in 200 ml. of THF, and the solution allowed to stand at room temperature for 2 'hours. The precipitated urea is removed by filtration, and the filtrate is evaporated in vacuo to a residue and flushed with Skelleysolve B. The residual oily anhydride is used without purification in the next step.

B. 't-BUTYL 2METHYL-5-METHOXY-3-LNDOLYL- ACETATE t-Butyl alcohol (25 ml.) and fused zinc chloride (0.3 g.) are added to the anhydride from part A. The solution is refluxed for 16 hours and excess alcohol is removed in vacuo. The residue is dissolved in ether, washed several times with saturated bicarbonate, water and saturated salt solution. After drying over magnesium sulfate, the solution is treated with charcoal, evaporated, and flushed several times with Skelleysolve B for complete removal of alcohol. The residual oily ester (18 g., 93%) is used without purification.

C. t-BUTYL[1-(BENZOFURAN--CARBONYL)-2-METHYL 5-METHOXY 3-I NDOLYL]ACETATE A stirred solution of ester (18 g., 0.065 mole) in dry dimethylformamide (450 ml) is cooled to 4 in an ice bath, and sodium hydride (4.9 g., 0.098 mole, 50% susp.) is added in portions. After minutes, p-nitrophenyl benzofuran-4-carboxylate (prepared by the procedure of Example 3A using benzofuran-4-carboxylic acid instead of 1 methylindole-2-carboxylic acid (0.085 mole) in dimethylformamide) is added dropwise during 10 minutes, and the mixture is stirred for 4 hours at 0 C. under nitrogen followed by overnight at room temperature. The mixture is then poured into an ice water ether mixture containing a few ml. of acetic acid. The layers are separated and the aqueous phase is extracted with ether. The ether solutions are combined, dried over sodium sulfate and to the solution is added a saturated solution of dry HCl in ether. The ether is decanted, leaving a heavy oil which is washed with water followed by aqueous NaHCO solution. The product is then extracted with ether and the extract is dried over anhydrous Na SO Evaporation of the ether yields t-butyl (benzofuran-4- carbonyl)-2-methyl-5-methoxy-S-indolyl acetate which is purified by chromatography on a column of neutral alumina using ether-petroleum ether (v./v. 2060%) as the eluent.

D. [1- (BENZOFURAN--CARBONYL) 2-METHYL-5-METH- OXY'3-LND OLYL ACETIC] ACID A mixture of 13 g. of the ester prepared in part C and 0.1 g. powdered porous plate is heated in an oil bath at 210 with magnetic stirring under a blanket of nitrogen for about 2 hours. No intensification of color (pale yellow) occurs during this period. After cooling under nitrogen, the product is partitioned between a mixture of ether and dilute ammonium carbonate. The aqueous solution is filtered with suction to remove ether, neutralized with acetic acid, and diluted with ethanol to precipitate the zwitter ion. The crude product, l-(benzofuran-4-carbonyl)-2-methyl-5-methoxy-3-indolyl acetic acid is recrystallized from aqueous ethanol and dried in vacuo.

EXAMPLE 7 Ethyl a- [1-(benzothiazole-G-carbonyl) -2-methyl-5- methyl-3-ind0lyl] -propi0nate The procedure of Example 3A is followed, using benzothiazole-6-carboxylic acid instead of l-methylindole-Z- carboxylic acid to produce p-nitrophenyl 'benzothiazole-6- carboxylate. This is then used in the procedure of Example 3B, using ethyl ot-(Z-methyl-5-methoxy-3-indolyl)- propionate instead of methyl-2-methyl-5-methoxy-3-indolyl acetate, to produce ethyl a-[1-(benzothiazole-6- carbonyl) -2-methyl-5-methoxy-3 -indolyl] -propionate.

EXAMPLE 8 [1-(Z-metlzyl-benzothiazole-S-carbonyl) -2-methyl-5- meth0xy-3-ind0lyl-acetic] acid A. A solution of 15 g. of methyl (Z-methyl-S-methoxy- I 3-indolyl)-acetate and 0.2 g. ofsodium in 60 ml. of benzyl alcohol is slowly fractionated over a period of 4 /2 hours through a Vigreux column to remove methanol. The excess benzyl alcohol is then removed by distillation at 60 C. (2.5 mm.) to give a residue of 18.6 g. of benzyl- (2-methyl-5-methoxy-3-indolyl)-acetate.

B. 10 g. of the benzyl ester obtained above is added to 6.6 g. of 51% sodium hydride-mineral oil emulsion in 260 ml. of dimethylformamide according to the procedure of Example 2. This mixture is treated as described in that example with Z-methyl-benzothiazole-5- carboxy chloride (prepared by heating with excess SOCI followed by removal of excess thionyl chloride in vacuo) and the reaction mixture Worked up by the above-de scribed process using a chromatographic column of 340 g. of alumina and eluting with 2030% ether in petroleum ether. From these eluates there is obtained benzyl [1-(Z-methyl-benzothiazole -5- carbonyl) 2-methyl-5- methoxy-3-indolyl] -acetate.

C. 1.75 g. of the ester obtained in Part B above is added to 20 ml. of ethyl acetate containing a drop of acetic acid and reduced catalytically at room temperature in the presence of palladium on charcoal catalyst. When the reduction is complete the catalyst is removed by filtration and the filtrate evaporated to a crystalline residue. This residue is recrystallized from aqueous ethanol to give l-(2-methyl-benzothiazole-5-carbonyl)-2- methyl-5-methoxy-3-indolyl acetic acid.

EXAMPLE 9 [1- benzis0xaz0le-3-carb0nyl) -2-methyl-5-meth0xy-3- indolyl acetic] acid The procedure of Example 6 is followed using benzisoxazole-3-carboxylic acid in place of benzofuran-4-carboxylic acid, to produce 1-(benzisoxazole-3-carbonyl)-2- methyl 5 methoxy-3-indolyl acetic acid. Similarly, when any of the other acids (indicated in Example 4) are used in equivalent quantity in place of benzofuran-4- carboxylic acid, the corresponding 1-acyl-2-methyl-5- methoxy-3-indolyl acetic acid is formed.

13 EXAMPLE 10 [l benzaxazole-S-carbonyl) -2-methyl5-metll0xy-3- ind olyl] -a-propion ic acid A. 2-METHYL-5-METHOXY-3-INDOLYL-a-PR OPIONIC ANHYDRIDE Dicyclohexylcarbodiimide (9 g. 0.044 mole) is dissolved in a solution of 2-methyl-5-methoxy-3-indolyl-apropionic acid (21 g., 0.09 mole) and 200 ml. of THF, and the solution is allowed to stand at room temperature for 2 hours. The precipitated urea is removed by filtration, and the filtrate is evaporated in vacuo to a residue and flushed with Skellysolve B. The residual oily anhydride is used without purification.

B. t-BU'IYL auETHYL--METHoXY-3-INDOLYL-a- PROPIONATE t-Butyl alcohol (25 ml.) and fused zinc cholride (0.3 g.) are added to the above anhydride. The solution is refluxed for 16 hours, and excess alcohol is removed in vacuo. The residue is dissolved in ether, washed several times with saturated bicarbonate, water and saturated salt solution. After drying over magnesium sulfate the solution is treated with charcoal, evaporated, and flushed several times with Skellysolve B for complete removal of alcohol. The residual oil ester (14 g. is used without purification.

C. t-BUTYL[1(BENZOXAZOLE-5-CARBONYL)-2-METHYL- 5-METHOXY-3-INDOLYL] -CLPROPIONATE A stirred solution of ester from part B (20 g., 0.69 mole) in 450 ml. of dry dimethylformamide is cooled to 4 in an ice bath and sodium hydride (5.2 g., 0.10 mole, 50% susp.) is added in portions. After the mixture is stirred for minutes, a DMF solution of benzoxazole-S- carboxy chloride (0.091 mole) (prepared by heating the acid in with SOCl follower by evaporation in vacuo) is added in portions during 10 minutes, and the mixture is stirred for 7 hours at room temperature without replenishing the ice bath. The mixture is then poured into 1 l. of 5% acetic acid, extracted with ether, washed thoroughly with water, bicarbonate, saturated salt solution, dried over magnesium sulfate, treated with charcoal, and evaporated in vacuo to a residue. This is dissolved in ether, mixed with 100 g. of acid-washed alumina, and evaporated in vacuo to dryness. The residue is placed above a column of 300 g. of neutral alumina in Skellysolve B. After washing with Skellysolve B, the product is eluted with 5% ether-Skellysolve B.

D. [1-(BENZOXAZOLE-S-CARBONYL)"2-METHYL-5- METHOXY-3-INDOLYL] aPROPIONIC ACID The pyrolysis is carried out in the same manner as with t-butyl 1-benzofuran-4- carbonyl) -2-methyl-5 -methoxy3 indolyl acetate (of Example 6D). The product is recrystallized from aqueous ethanol or benzene-Skellysolve.

EXAMPLE 11 Methyl (Z-metlzyl-S-nitro-S-indolyl) acetate A solution of 40 g. of levulinic acid in 300 ml. of hot water is added to a solution of 65 g. of p-nitrophenylhydrazine hydrochloride in 700 ml. of hot water with stirring. After about one-half hour, the hydrazone derivative is collected in a filter, washed with water and dried at 110 in vacuo. The yield is 84 g., M.P. 175-179".

An amount of 42 g. of the above hydrazone is added to a solution of 120 g. of fused zinc chloride in 100 ml. of absolute ethanol and the mixture is refluxed for 18 hours. The cooled solution is poured into dilute hydrochloric acid with stirring, and the insoluble gummy material separated is extracted with hot ethanol. The ethanolic extract is evaporated in vacuo to a syrup, which is redissolved in ether. The ether solution is extracted with 10% sodium carbonate several times. Acidification of the aqueous solution gave a crude product which recrystallizes from chloroform to give (2-methyl-5-nitro-3-indolyl)acetic acid, M.P. 238.

The above acid is treated with a mixture of 3 g. of sulfuric acid and 40 ml. of methanol at the reflux temperature for 6 hours. The methyl ester is obtained as a yellow crystalline product, M.P. 132-40 after recrystallization from benzene.

Similarly, methyl ot-(2-methyl-5-nitro-3-indoly1)-propionate is prepared by using an equivalent amount of amethyl levulinic acid as the starting material.

EXAMPLE 12 Methyl (2-methyl-5-amin0-3-ind0lyl) acetate 3 g. of methyl(Z-methyl-5-nitro-3-indolyl)acetate is dissolved in 300 ml. dry methanol and reduced in hydrogen in an autoclave with Raney nickel as catalyst. After the theoretical amount of hydrogen is taken up the catalyst is removed by filtration. The catalyst and reaction flask are Washed with methanol. The methanol. solution is evaporated to dryness. The product is crystallized from benzene, M.P. 144-145".

Micr0analysis.Calcd.: C, 66.03; H, 6.47; N, 12.84. Found: C, 65.96; H, 6.29; N, 12.56.

EXAMPLE 13 Methyl [2-methyl-5- (1 '-pyrrolidin0 -3-3-ind0lyl] acetate In a 125 ml. flask is placed ml. of ethanol. To this is added 1.0 g. of methyl (2-methyl-5-amino-3-indolyl) acetate, 0.99 g. of 1,4-dibromobutane and 0.975 g. of anhydrous sodium carbonate. This mixture is stirred at reflux temperature in a nitrogen atmosphere for 6 hours. The reaction mixture is then filtered and. the filtrate is concentrated in vacuo to a small volume and diluted with ether. This solution is then washed with water 2X, dried with anhydrous sodium sulfate and concentrated in vacuo to dryness. The product is absorbed on 6 g. of silica gel. The product is then chromatographed over 30 g. of silica gel using as elutant from v./v. 3:1 ether- :pe'troleurn ether to ether. The eluted material is combined and crystallized from benzene-Skellysolve B., M.P. 117- 118.

Micr0arzalysis.Calcd.: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.77; H, 7.72; N. 10.00.

When ethylene di bromide is used instead of dibromobutane, the product obtained is the 5-(1-azacyclopropyl) indolyl compound.

EXAMPLE 14 Methylfl- (1-methylind0le-2-carb0nyll -2-methyl-5-(1- pyrrolidino -3-I'nd0lyl] acetate The procedure of Example 3B is followed using methyl [2-methyl-5-(1'-pyrrolidino)-3-indolyl]acetate in place of the indole ester from 3A used in that example to produce methyl [1 (1 methylindole-2-carbon.yl)-2-methyl-5-(1- pyrrolidino) -3-indolyl] acetate.

EXAMPLE 15 Methyl [1 (1 -methylina'ole-Z-carbonyl) -2-methyl-5- nitrofi-inaoly l] acetate In a dried 250 ml. flask is placed 3.9 g. of methyl-(2- methyl-5-nitro-3-indolyl) acetate in '125 ml. dry dirnethylf-ormamide. To this solution cooled to 0 C. is added 0.8 g. of 50% sodium hydride-mineral oil. This is stirred under nitrogen for 30 minutes. To this is added dropwise 4.85 g. of p-nitrophenyl 1-methylindole-2-carboxylate in 15 ml. of dry dimethylformamide over a 5-minute period. The reaction mixture is stirred 4 hours at 0 C. under nitrogen and then stirred overnight at room temperature under nitrogen. It is then poured into an ice water-ether solution containing a few milliliters of acetic acid. The ether layer is separated and the aqueous layer is washed with ether. To the combined ether layers after drying over Na SO is added a saturated solution of hydrogen chloride gas in dry ether. The ether layer is decanted and 15 the residue is washed with ether followed by an addition of aqueous NaHCO solution. The alkaline solution is then extracted with ether and the ether layer is dried and evaporated in vacuo. The product, methyl [l-(l-methylindole 2-carbonyl)-2-methyl-5-nitro-3-indolyl]acetate is crystallized from dry ether-Skellysolve.

EXAMPLE 16 Methyl [1(1-methylindole-Z-carbonyl)-2-methyl-5- dimethylamin-3-ind0lyl] acetate To a solution of 0.573 g. of methyl-a-[l-(l-methylindole-2-carbonyl)-2-methyl-5-nitro-3-indolyl] acetate in 20 ml. of distilled dimethoxyethane is added 1.5 ml. of glacial acetic acid and 0.5 ml. of a 37% solution of aqueous formaldehyde. This mixture is reduced with Raney nickel at 40 p.s.i. and room temperature. After the theoretical amount of hydrogen has reacted, the reaction mixture is filtered, concentrated in vacuo to a small volume and diluted with ether. The ether solution is washed with sodium bicarbonate, then with Water, dried with anhydrous sodium sulfate and concentrated in vacuo. The product is methyl [1-(1 methylindole-Z-carbonyl)-2-methyl 5- dimethylamino-3-ind-olyl] acetate.

EXAMPLE 17 Methyl [1-(1-methylindole-Z-carbonyl)-2-methyl-5- acetamina-3-indolyl] acetate To .573 g. of methyl [1-(lmethylindole-Z-carbonyl)-2- methy1-5-nitro-3-indoly1] acetate in 30 ml. of anhydrous ethyl acetate is added 0.306 g. acetic anhydride. The mixture is reduced with Raney nickel at room temperature and 40 p.s.i. After the theoretical amount of hydrogen has been absorbed, the catalyst is removed by filtration. The solution is concentrated in vacuo to a small volume and poured into an ice Water-ether mixture. The ether layer is separated and the aqueous layer is Washed with ether. The combined ether extracts are washed with sodium bicarbonate followed by water, dried with anhydrous sodium sulfate and concentrated in vacuo to dryness. The product, methyl [1-(1-methylindole-2-carbonyl)-2-methyl- 5-acetamino-3-indolyl] acetate, is crystallized from benzene and ether.

EXAMPLE 18 Benzyl (2-methyl-5-nitr0-3-ittd0lyl) acetate In a dry 250 ml. flask is placed 80 ml. dry benzene and 20 ml. benzyl alcohol. To this is added 3.0 g. of 2- methyl-5-nitro-3-indolyl acetic acid and 0.2 g. of ptoluenesulfonic acid. This slurry (which clears on heating) is heated to reflux under nitrogen. The water formed during the reaction is collected in a Stark and Dean tube. The reaction is stopped when the distillate is clear (about 2 hours). The excess benzyl alcohol is removed in vacuo. The residue is dissolved in benzene and washed with sodium bicrabonate followed by water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The product is absorbed on 15 g. of acid-washed alumina and chromatographed over 75 g. of acid-washed alumina. The product is eluted with v./v. 1:13:1 ether-benzene. The eluate is evaporated and the combined product is crystallized from benzene-Skellysolve B, MP. 147448".

Microanalysis.-Calc.: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.83; H, 4.77; N, 8.52.

EXAMPLE 19 Benzyl [1-(l-methylind0le-2-carb0nyl)-2-methyl-5- nitr0-3-irta'0lyl] acetate In a dry 125 ml. flask is placed 3.0 g. of benzyl-(2- methyl-5-nitro-3-indolyl) acetate in 60 ml. of dry dimethylformamide. To this solution, cooled to 0 C. in a nitrogen atmosphere is added 0.475 g. of 50% sodium hydride-mineral oil. This is stirred for 30 minutes. Then 2.69 g. of p-nitrophenyl l-rnethylindole-2-carboxylate in mlf dry dimethylformat e is added dropwise over a 5-minute period. The reaction mixture is stirred at 0 C. for 4 hours under a nitrogen atmosphere followed by stirring at room temperature under nitrogen overnight. It is then poured into an ice water-ether mixture. The ether layer is separated and the aqueous layer is washed with ether. The combined ether extracts are acidified with an ether solution of dry hydrogen chloride and the ether is decanted. The residue is Washed with ether and then stirred with aqueous NaHCO solution. The alkaline mixture is extracted with ether and the extracts are dried with anhydrous sodium sulfate and concentrated in vacuo to dryness. The product, benzyl [l-(l-methylindole-Z- carbonyl)-2-methyl-5-nitro-3-indolyl] acetate, is cry-stallized from benzene-Skellysolve B.

EXAMPLE 2O Methyl 0L- [1-(1-methylind0le-Z-carbonyl) -2-methyl-5- am in0-3 -z'nd0lyl propt'onate 0.025 mole of methyl ot-[1-(l-methylindole-Z-carbonyl)-2-methyl-5-nitro-3-indolyl]propionate in ml. of ethanol is hydrogenated in the presence of mg. of 10% palladium or charcoal catalyst at 40 p.s.i. at room temperature. After 0.075 m. of hydrogen has been consumed, the hydrogenation is stopped, and the solution filtered to remove the catalyst. The filtrate is concentrated to dryness in vacuo to give methyl a[l-(l-rnethylindole- 2-carbonyl)-2-methyl-5-amino-3-indolyl]propionate.

EXAMPLE 21 Methyl [1-(4-hydroxy-5-benz0faran carb0nyl)-2- methyl-5-meth0xy-3-ind0lyl]acetate A. 4-BENZYLOXYBENZOFURAN-5-CARBOXYLIC ACID To 0.1 mole of ethyl-4-hydroxybenzofuran-S-carboxylate in 300 ml. of methanol is added an excess of potassium carbonate and 0.2. mole of benzylchloride, and the mixture is allowed to reflux for 6 hours. The mixture is concentrated in vacuo, poured into 400 ml. of Water and extracted with 200 ml. of ethyl ether. The aqueous layer is then treated with a slight excess of 1.0 N HCl to precipitate 4-benzyloxy-benzofuran-S-car boxylic acid.

B. p-NITROPHENYL The procedure of Example 3A is followed, using 1- methylindole-Z-carboxylic acid to produce p-nitrophenyl- 4-benzyloxybenzofuran-S-carboxylate.

o. METHYL 1- (2-METHYL-4BENZYLOXYBENZOFURAN- 5-CARBONYL) -2-METHYL-5-METHOXY 3 LNDOLYLL ACETATE The procedure of Example 3B is followed, using pnitrophenyl-4-benzyloxy-benzofuran 5 carboxylate in place of the 1-rnethylindole-2-carboxylate used therein. The product is [l-(4-benzyloxy-benzofuran-5-carbonyl)- 2-methyl-5-methoxy-3-indolyl] acetic acid.

D. METHYL 1- 4-HYDROXYBENZOFURAN-5-CARB ON- YL) -2-METHYL-5-METHOXY-3-IJNDOLYL] ACETATE A solution of 0.1 mole of the product of Part D in ml. of methanol is shaken with 3 g. of palladium on charcoal and hydrogen until hydrogen uptake ceases. The catalyst is filtered and the filtrate is taken to dryness in vacuo to yield methyl[1-(4-hydroxybenzofuran-S-carbonyl -2-methy1-5-methoxy-3 -indolyl] acetate.

E. When the procedures of Parts A, B, C, and D are followed, using 1-methy1-3-hydroxybenzofuran-4-carboxylic acid, 2-acetyl-4-hydroxybenzofuran-S-carboxylic acid, 4-hydroxy 7 phenylbenzofuran 6 carboxylic acid, 2- bromo-6-hydroxy-3-methylbenzofuran-7-carboxylic acid, 7-benzoyl-5-chloro-6-hydroxy-3-methyl-2-coumarilic acid, and S-cyano-1-hydroxyindole-2-carboxylic acid in place of 4-hydroxybenz-ofuran-5 -carboxylic acid, the corresponding l-acylindole compounds are obtained. When using the cyanohydroxyindole carboxylic acid, the 3-cyano is converted to the 3-aminomethyl radical in Part C of the above example.

1 7 EXAMPLE 2.2

A. Methyl[1-(1-methylindole-Z-carbonyl) 2 methyl-5- bis({3-hydr0xyethyl)amin0-3-ind0lyl]acetate A mixture of 0.02 mole of met-hyl-a-[1-(1-methylindole- 2-carbony1) -2-methyl-5-amino-3 -indolyl] propionate, 0.044 mole of ethylene oxide and 0.03 mole of acetic acid in 300 ml. dimethoxyet-hane is heated to 100 for 18 hours in an autoclave. The mixture is then diluted with water and filtered to yield crude methyl[1-(l-methylindole-Z- carbonyl)-2-methyl 5 bis(,8-hydroxyethyl)amino 3-indolyl]propionate.

When an equivalent amount of propylene oxide is used in the above procedure in place of the ethylene oxide, there is obtained methyl[1-(l-methylindole-2-carbonyl)- Z-methyl-S-bis(hydroxypropyl)amino 3 indo1yl1propionate.

B. Methylfl-(l-melhylindole 2 carbonyl) 2 methyl- 5 -(4 -m ethyl-1 '-piperazinyl) -3-ind0lyl] acetate The product of A is stirred at in pyridine with two mole proportions of p-toluenesulfonyl chloride until the reaction is substantially complete. The mixture is poured into water and the S-bis (p-toluenesulfonyloxyethyl)amino compound is isolated. This is dissolved in benzene and one .mole proportion of methylamine is added. The mixture is allowed to stand at room temperature for 3 days. The mixture is poured into iced water containing two equivalents of sodium carbonate and extracted with ether immediately. Evaporation of the ether yields methyl[1- (1-methylindole-2-carbonyl)-2-methy1 5 (4'-methy l-1'- piperazinyl) -3-indolyl] acetate.

Either of the above products that form part A or part B, when used in the procedure of Example 8, gives the corresponding free acid.

EXAMPLE 23 Methyl[1 (5,6 dihydroxyindole 3 carbonyl) 2- methyl-fi-meth0xy-3-ind0lyl]acetate A. METHYL[1-(5,fi-DIBENZYLOXYLNDOLE-3-CARBONYL- 2METHYL-5-METHOXY-3-INDOLYL] ACETATE The procedure of Examples 5A, 5B, 5C and 5D is fol lowed, using 3 equivalents of benzyl chloride and ethyl- 5,6-dihydroxyindole-3-carboxylate in place of methoxymethyl chloride and ethyl-benzimidazole-2-carboxylate, respectively, as indicated in the procedure of Example 5A and the product thereof successively in 5B, 5C and 5D to produce methyl[1-(5,6-dibenzyloxyindole-3-carbo-nyl)- Z-methyl-S-methoxy-3-indolyl] acetate.

B. METHYL[1-(5,6-DIHYDROXYLNDOLE-3-CARBONYL)- 2-METHYL-5-METHOXY-3-I-NDOLYL] ACETATE A solution of 0.1 mole of the product of Part A in 150 ml. of methanol is shaken with 3 g. of palladium on charcoal and hydrogen until hydrogen uptake ceases. The catalyst is filtered and the filtrate is taken to dryness in vacuo to yield met-hy1[1-(5,6-dihydroxyindole-3-carbonyl) -2-methyl-5-methoxy-3-indolyl]-acetate.

EXAMPLE 24 Methyl[1(I-melhylindole-Z-carb0nyl) 2 methyl 5- (4-m0rph0linyl)-3-indolyl]acetate A solution of tosyl chloride (0.1 mole) in 200 ml. benzene is added dropwise with stirring to a solution of methyl a-[1-( 1-methylindole-2-carbonyl) -2-methyl-5-bis- (B-hydroxyethyl)amino-3-indolyl]acetate (0.1 mole) and pyridine (0.3 mole) in 300 m1. benzene at room temperature over a period of one hour. The mixture is then heated under reflux for 3 hours, Washed with water, dried over sodium sulfate and evaporated to a syrup. Chromatography of the syrup on an alumina column using 3O 50% (v./v.) ether in petroleum ether as the eluent gives methyl[1 (1 methylindole-Z-carbonyl)-2-methyl-5-(4'- morpholinyl -3-indo-lyl] acetate.

The above product, when used in the procedure of Example 8, gives the corresponding free acid.

EXAMPLE 25 A. 2-methyl-S-cyanod-indolylacetic acid methyl ester B. Methyl ot-[1(1-methylindole-Z-carbonyl) 2 methyl- 5-cyan0-3-z'ndolyl]acetate Acylation of the ester (prepared in Example 25A above) in dimethylformamide with sodium hydride and p-nitrophenyl-l-methylindole-Z-carboxyl-ate by the procedure of Example 3, gives methyl[l-(l-methylindole-Z- carbonyl) -2-methyl-5-cyano-3 -indolyl] acetate.

C. Methyl ot-fl-(l-mezhylindole 2 carbonyl) 2 methyl- 5-amin0methyl-3-ind0lyl] acetate The S-cyano ester prepared in Example 253 is hydrogenated in ethanol in the presence of Raney nickel and 3 moles of anhydrous ammonia at 2000 p.s.i. at room temperature to give, after filtration of the catalyst and evaporation of the reaction mixture, methy1[1-(l-methylindole- 2-carbonyl)-2-methyl-S-aminomethyl 3 indolyll-acetate which can be recrystallized from aqueous ethanol.

D. Methyl[J-(I-methylindole 2 carbonyl) 2 methyl- 5-dimethylamin0methyl-3-indolyl]acetate Treatment of the above ot-aminomethylindole with 2 moles of methyliodide gives the S-dimethylaminomethyl derivative. When ethyliodide is used in place of methyliodide, the S-diethylaminomethyl derivative is obtained.

When the products of Examples 25C and 25D above are used in the procedure of Example 8, the corresponding free acids are obtained.

EXAMPLE 26 u-[1-(1metlzylindole 2 carbonyl) 2 methyl -5 metlzoxy-3-indolyl]butyric acid When the procedure of Examples 1 and 2 are followed using ethyl a-ethyl levulinate in place of ethyl tat-methyl levulinate, there is obtained successively ethyl a-(2-methyl- 5-methoxy- 3-indolyl)butyrate and ethyl a-[l-(l-methylindole 2 carbonyl)-2-me-thyl-5-met-hoxy-3-indolyl]butyrate. When the latter product is used in the procedure of Example 9, the corresponding butyric acid derivative is obtained.

The starting ethyl wethyl levulinate is prepared by alkylation of the sodio derivative of ethyl ace-toacetate in ethanol with 1 m. of ethyl u-bromobutyrate, followed by hydrolysis and decarboxylation. The a-ethyl levulinic acid obtained is re-esterified with 2 N ethanolic hydrogen chloride at reflux temperature for 18 hours.

EXAMPLE 27 0.02 mole of tx-[1-(benzothiazole-S-earbonyl)-2-methyl-5-methoxy-3-indolyl] acetic acid is added to 50 ml. of water which has been flushed with nitrogen. The slurry is stirred under nitrogen and 20 ml. of 1.05 N sodium carbonate added with stirring. When a clear solution is obtained, a solution of 2.2 g. of Al (SO .18H O in 8 ml. of Water is added with vigorous stirring. The mixture is stirred until it is homogeneous and the solid aluminum salt of [1-(1-methylindole-2-carbonyl)-2-methyl-5- methoxy-3-indolyl1acetic acid is recovered by filtration and washed with water and ethanol.

19 In asimilar fashion, there may be prepared the sodium and aluminum salts as well as other salts, such as the potassium, iron and magnesium salts, of the various (3- indolyl)aliphatic acids described in the accompanying examples.

EXAMPLE 28 [I-(1-methylind0le-2-carb0nyl)-2-methyl-5-meth0vcy-3- indolyllacetic anhydride The procedure of Example 6A is followed using [1-(1- methylindole 2-carbony1)-2-methyl-5-tmethoxy-3-indolyl] acetic acid in place of the l-unsubstituted acid. The product, [1 (l methylindole 2-oarbonyl)-2-methyl-5- methoxy-3-indolyl]acetic anhydride, is found on testing to be about equal to the free acid in the alleviation of inflammation.

When any of the other l-substituted free indolyl acids herein described are used in the procedure of Example 6A, the corresponding anhydride is obtained.

EXAMPLE 29 Ethyl a- [1-(I-methylind0le-2-carb0nyl) -2-methyl- 5 -ethxy-3-ind0lyl propionate The procedure of Example 1A is followed using an equivalent quantity of p-ethoxyphenylhydrazine hydrochloride in place of the methoxyphenylhydrazine to give ethyl [a-( 2-methy1-5-ethoxy) -3-indolyl]propionate. When this is used in the procedure of Example 3, there is obtained ethyl u-[1-(1-methylindole-2-carbonyl)-2-methyl- -methoxy-3-indolyl]propionate. This product, when used in the procedure of Example 8, yields the corre sponding free a-indolyl propionic acid.

Similarly, when p-propoxy, p-butoxy, p-benzyloxy, p-4- methylbenzyloxy, p-4 methoxybenzyloxy, p-4-chlorobenzy-loxy phenylhydrazine are used in the above procedures, the correspondingly 5-substituted indolyl acids are obtained. When the [l-(1-methylindole-2-carbonyl)-2- methyl-S-benzyloxyor substituted benzyloxy)-3-indolyl] propionic acids so prepared are subjected to catalytic hydrogenation over palladium, there is obtained a-[l-(lmethylindole Z-carbonyl)-2-methy1-5-hydroxy-3-indolyl] propionic acid.

When the procedure of Example 1A is followed using in place of the p-methoxyphenylhydrazine, equivalent amounts of p-ethylphenylhydrazine, p-butylphenylhydra zine, p-trifluoromethylphenylhydrazine, p-chlorophenylhydrazine and p-fluorophenylhydrazine (each obtainable by diazotization of the corresponding p-substituted aniline and reduction of the diazo) and the resultant indolyl ester is acylated by the procedure of Example 3 and further treated by the procedure of Example 8, the corresponding S-substituted indolyl esters and acids are obtained.

When the procedure of Examples 1A, 3 and 8 are followed, starting with phenylhydrazine, the corresponding S-unsubstituted indolyl esters and acid are produced.

EXAMPLE 30 [1-(I-methylindole-3-carb0nyl) -2-methyl-5- methoxy-3-indo lyl] acetamide To a suspension of 1.0 g. of 50% sodium hydride in 80 ml. benzene is added 4.4 g. of Z-rnethyl-S-methoxy- 3-indolylacetamide with stirring. Twenty ml. of dimethyl formamide is then added, followed by 3.84 g. of methylindole-3-carboxy chloride twenty minutes later. The re action mixture is stirred at room temperature for one hour and then poured into 400 ml. of ice and water. The precipitate is collected on a filter. The crude product is recrystallized from ethyl acetate twice.

EXAMPLE 3 1 [1-(1-methylind0le-3-carbonyl) -2-methyl-5- meth0xy-3-ind0lyl] acetic acid To a solution of 3.7 g. of [1-(1-methy1indole-3-carbonyl)-2-methyl-5-1methoxy-3-indolyl]acetamide in 50 ml. di-methoxyethane containing 1 ml. of 12 N hydrochloric 20- acid at 0 is added 0.7 g. of sodium nitrite with stirring. After gas evolution has subsided the mixture is neutralized with dilute ammonium hydroxide, concentrated in vacuo and then diluted with ethanol to precipitate the product, which is purified by recrystallization from aqueous ethanol.

EXAMPLE 32 The procedure of Example 1A is followed using an equivalent quantity of each of the following phenylhydrazines in place of the p-methyoxyphenyl hydrazines; p-dimethylsulfonamidophenylhydrazine, p-benzylmercaptophenylhydrazine, p-vinylphenylhydrazine.

When the resulting indolyl acid is acylated by the procedure of Example 3, the corresponding l-nicotinoyl indolyl acids are obtained.

EXAMPLE 3 3 Methyl [1 benzothiaz0le-5 carbonyl -2-methyl-5- ally l0xy-3-ind0ly l acetate A. METHYL-5-HYDROXY-2METHYL-3-LNDOLYL ACETATE A mixture of 10 g. of methyl-5-methoxy-2-methyl-3- indolyl acetate and 50 g. of pyridine hydrochloride is heated at 180 under nitrogen for 15 minutes. The reaction mixture is then cooled to about 50, dissolved in 150 ml. of 1.5 N methanolic hydrogen chloride and refluxed for 2 hours. After cooling, the solution is concentrated in vacuo, poured into water and extracted with ether. The ethereal solution is washed with water and extracted three times with 50 ml. of 5% sodium hydroxide. The combined aqueous extract is acidified to pH 6 and extracted with ether. After drying over sodium sulfate, the ethereal solution is evaporated to give methyl 5-hydroxy-2-methyl-3-indolyl acetate, recrystallized from benzene, M.P. 158-l70 (3.4 g.).

B. METHYL-2-METHYL-5-ALLYLOXY-3-INDOLYL ACETATE A mixture of 3.4 g. of the S-hydroxyindole, 2.4 g. of allylbromide and 7.5 g. of potassium carbonate is stirred at room temperature to 56 for l to 6 hours. The reaction mixture is filtered, concentrated in vacuo to a syrup and chromatographed on 60 g. of silica gel, using v./v. 50% ether in petroleum ether as eluent to give 0.7 g. of methyl 5 allyloxy-2-methyl-3-indolyl acetate as an oil.

0. [1-(BENZOTHIAZOLEh-CARBONYL)-2-METHYL-5- ALLYLOXY-3-INDOLYL]ACETATE The producedure of Example 3 is followed, using the above 5-allyloxy compound in place of the 5-methoxy compound to give methyl-l-(p-chlorobenzoyl-2-methyl-5- allyloxy-3-indolyl)acetate, recrystallized from benzene- Skellysolve B.

Similarly, when allyl bromide is replaced by an equivalent amount of cyclopropylmethyl bromide, cyclobutylmethyl bromide and isopropyl bromide, the corresponding S-cyclopropylmethoxy, 5-cyclobutylmethoxy, 5-isopropoxy analogs are obtained.

EXAMPLE 34 3-triflu0romethylphenylhydrazine 250 ml. of' chilled concentrated hydrochloric acid is slowly added with stirring, to 0.40 of a mole of freshly distilled 3-aminobenzotrifluoride, which is kept cooled in an ice salt bath. When the temperature of the above suspension is 0, a precooled solution of 0.40 of a mole of sodium nitrite in 125 ml. of water is added through a separating funnel, whose tip is immersed below the surface of the suspension. The addition is carried out over minutes, maintaining the reaction below 3. A chilled solution of 0.89 mole of stannous chloride dihydrate in 200 ml. of concentrated hydrochloric acid is then added dropwise to this stirred and cooled diazonium solution, over a period of three hours. During this addition, the temperature is maintained at 05 and after the addition, the solution is stirred for an additional hour at The resulting solid is collected by filtration, pressed as dry as possible and then shaken with 700 ml. of 25% sodium hydroxide. The yellow mixture obtained is allowed to stand overnight at room temperature. The mixture is then extracted with three 300 ml. portions of benzene. The combined filtered benzene solution is dried over 2030 g. of potassium hydroxide. Distillation, under vacuum, of this benzene solution gives 3-trifluoromethylphenylhydrazine.

When equivalent amounts of 2-aminobenzotrifiuoride, 4-methoxy-3-trifiuoromethylaniline, 4-methoxy-2-trifluoromethylaniline, or 4-methyl-3-trifiuoromethylaniline is employed in the above procedure in place of 3-aminobenzotrifluoride, there is obtained 2-trifiuoromethylphenylhydrazine, 4-methoxy-3-trifluoromethylphenylhydrazine, 4- methoxy-2-trifluoromethyl hydrazine or 4-methyl-3trifluoromethylphenylhydrazine, respectively.

EXAMPLE 35 Methyl-4 and d-trifluoromethyl-3-indolylacelate 0.2 mole of methyl y, y-dimethoxybutyrate is added, dropwise with stirring, to a solution of 0.2 mole of 3-trifiuoromethylphenylhydrazine in 75 ml. of 50% acetic acid. The mixture is allowed to stir at room temperature for three hours, and then 300 ml. of water is added. The crude hydrazone which separates out is collected and dried in vacuo. 0.04 mole of the dried hydrazone is then intimately mixed with 0.85 mole of freshly fused zinc chloride. To this mixture is added, with stirring, for 5 minutes at room temperature, 135 ml. of glacial acetic acid and 5 ml. acetic anhydride. The mixture is then refluxed for one hour and cooled to room temperature. This resulting mixture is poured onto chopped ice and water and allowed to stand overnight in a refrigerator. The solid is collected and precipitated by filtration and chromatographed on acid-washed alumina and eluted with ether-petroleum ether (v./v. 550%). The two isomers which are obtained, namely, methyl-(4-trifluoromethyl-3- indolyl)aoetate and methyl-(6-trifluoromethyl-3-indolyl) acetate are diiferentiated by nuclear magnetic resonance spectroscopy.

When equivalent amounts of 4-methoxy-3-trifiuoromethylphenylhydrazine, or 4-methyl-3-trifluoromethylphenylhydrazine is employed in the above procedure in place of 3-trifluoromethylphenylhydrazine, there is obtained both isomers of each, namely, methyl (5-methoxy-4-trifiuoromethyl-3-indolyl)acetate, methyl (5-methoxy-6-trifiuoromethyl-3-indolyl)acetate, or methyl (5-methyl-4-trifiuoromethyl-3-indoly1)acetate, methyl (5-methyl-6-trifluo'romethyl-3-indolyl acetate, respectively.

Similarly, when equivalent amounts of 2-trifluoromethylphenylhydrazine, 4-methoxy-2-trifluoromethylhydrazine or 4-methyl-Z-trifluoromethylphenylhydrazine are employed in place of 3-trifluoromethylphenylhydrazine, there is obtained methyl-(7-trifluoromethyl-3-indolyl)acetate, methyl (5-methoxy-7-trifiuoromethyl-3-indolyl)acetate; or methyl (5-methy1-7-trifluoromethyl-3-indolyl)acetate, respectively.

EXAMPLE 36 Methyl a-[4- 0r 6-triflu0r0methyl-3-ind0lyl]propionate When the procedure of Example 41 is followed, using methyl-'y,'y-dimethoxy-a-methylbutyrate in place of methyl-'y,v-dimethoxybutyrate, there are obtained two isomers, namely, methyl a-(4-trifiuoromethyl-3-indolyl)propionate and methyl u-(6-trifluoromethyl-3-indolyl)propionate.

When equivalent amounts of 4-methoxy-3-trifluoromethylphenylhydrazine, or 4 methyl-3-trifluoromethylphenylhydrazine is employed in place of 3-trifiuoromethylphenylhydrazine, there are obtained both isomers of each, namely, methyl u-(5-methoxy-4-trifluoromethyl-3- indolyl)propionate, methyl a-(S-methoxy-6-trifluoromethyl-3-indolyl)propionate; methyl a-(5-methyl-6-trifluoromethyl-3-indolyl)propionate, respectively.

Similarly, when equivalent quantities of 2-trifiuoromethylphenylhydrazine, 4-methoxy-2-trifluoromethylphenylhydrazine or 4-methyl-2-trifluoromethylphenylhydrazine is employed in place of 3-trifluoromethylphenylhydrazine, there is obtained methyl u-(7*trifluoromethyl-3-indolyl) propionate, methyl or (5-methoxy-7-trifiuoromethyl-3-indolyl)propionate or methyl ot-(5-methyl-7-trifiuoromethyl- 3-indolyl)propionate, respectively.

EXAMPLE 37 Methyl (2-methyl-4 0r 6-triflu0r0methyl-3-ind0lyl)acetate When the procedure of Example 35 is followed, using methyl levulinate in place of methyl-'ygy-dimethoxybutyrate, there is. obtained two isomers, namely, methyl (2 methyl-4-trifiuoromethyl-3-indolyl)acetate and methyl (2- methyl-6-trifiuoromethyl-3 -indolyl) acetate.

When equivalent quantities of 4-methoxy-3-trifluoromethylphenylhydrazine, or 4-methyl-3-trifluoromethylphenylhydrazine is employed in place of B-trifluoromethylphenylhydrazine, there is obtained both isomers of each, namely, methyl (5-methoxy-2-methyl-4-trifluoromethyl-3- indolyl)acetate, methyl (5-methoxy-Z-rnethyl-6-trifluoromethyl-3-indolyl)acetate or methyl (2,5-dimethyl-4-trifluor0methyl-3-indolyl) acetate, methyl (2,5-dimethyl-6-trifiuoromethyl-Ii-indolyl)acetate, respectively.

Similarly, when equivalent amounts of 2-trifluoromethylphenylhydrazine, 4 methoxy 2 trifiuoromethylphenylhydrazine, or 4-methyl 2 trifluoromethylphenylphenylhydrazine is employed in place of 3-trifluoromethylhenylhydrazine, there is obtained methyl (2-methyl-7- trifiuoromethyl-B-indolyl)acetate, methyl (S-methoxy-Z- methyl 7 trifiuoro-methyl-3-indolyl)acetate, or methyl (2,5-dimethyl-7-trifluorornethyl-3-indolyl)acetate, respectively.

EXAMPLE 38 M ethyl u- (Z-methyltriflu0r0meflzyl-3-indolyl) propionate When the procedure of Example 35 is followed, using methyl-a-methyl levulinate in place of methyldimethoxybutyrate, there is obtained two isomers, namely, methylor (2-methyl-4-trifiuoromethyl-3-ind0lyl)propionate and methyl a (2methyl-6-trifiuoromethy1-3-indolyl)propionate.

When equivalent amounts of 4-methoxy-3-trifiuoromethylphenylhydrazine or 4 methyl 3-trifluoromethylphenylhydrazine is employed in place of 3-trifluoromethylphenylhydrazine, there is obtained both isomers of each, namely, methyl-ot-(5-methoxy-2-methyl=4-trifiuoromethyl- 3 indolyl)propionate, methyl-ot-(5-methoxy-2-methyl-6- trifluoromethyl-3-indolyl)propionate; or methyl a-(2,5-Cllmethyl 4 trifiuoromethyl 3 indolyl)propionate and methyl u-(2,5-dimethyl-6-trifluoromethyl-3-indolyl)propionate, respectively. 7

Similarly, when equivalent amounts of Z-trifluoromethylphenylhydrazine, 4 methoxy 2 trifiuoromethylphenylhydrazine, or 4-methyl-2-trifluoromethylphenylhydrazine is employed in place of 3-trifluoromethylphenylhydrazine, there is obtained methyl a-(2-methyl-7-trifluoromethyl-3-indolyl)propionate or methyl oc-(2,5-di methyl 7 trifluoromethyl-3-indolyl)propionate, respectively.

EXAMPLE 39 [1-(I-methylindole-2-carbonyl) -4-triflu0r0methyl-3- indolyl] acetic acid A. A solution of 0.05 mole of methyl-(4-trifluoromethyl-3-indolyl)acetate and 0.01 mole of sodium in 60 ml. anhydrous benzyl alcohol is slowly fractionated over a period of 4 /2 hours through a Vigreux column to remove methanol. The excess benzyl alcohol is removed by distillation at 60 and 2.5 mm. to give a residue of crude benzyl (4-trifluoromethyl-3-indolyl)acetate.

B. A suspension of 0.046 mole of 50% sodium hydridemineral oil in 250 ml. of dimethylformamide is stirred for 20 minutes under nitrogen, with ice-cooling. Then 0.035 mole of the benzyl ester obtained above in part A is added and the mixture stirred for 20 minutes. 0.046 mole of p-nitrophenyl-1-methylindole-2-carboxylate in 50 ml. of dimethylformamide is added dropwise over a period of 30 minutes. The mixture is stirred in an ice bath for 5 hours under nitrogen, then poured into a mixture of 500 ml. of ether, 5 ml. of acetic acid and 1 l. of iced water. The organic products are extracted with 3 x 300 ml. of ether. The ether solutions are combined and acidified with an ether solution of dry HCI. The ether is decanted and the residue is Washed with ether and then mixed with aqueous NaHCO The mixture is extracted with ether and the extracts are dried over sodium sulfate. The solution is then evaporated to near dryness and the residue charged onto a 300 g. alumina column. The 'benzyl[1- (1-methy1indole-2-carbonyl)-4- trifiuoromethyl-3-indolyl] acetate is eluted with etherpetroleum ether (550% v./v.).

C. 0.02 mole of the ester obtained in part B is added to 50 ml. of ethyl acetate containing a drop of acetic acid and is reduced catalytically at room temperature in the presence of palladium on charcoal catalyst. Upon completion of the reduction, the catalyst is removed by filtration and the filtrate evaporated to yield [l-( 1-methylindole-2-carbonyl)-4-trifluoromethyl-3-indolyl] acetic acid.

When the methyl esters described in Examples 36, 37 and 38 are used in the above procedures, the correspond ing [1-(1-methylindole-2-carbonyl)-3-indolyl]acetic or 3- indolyl-ot-propionic acid derivatives are obtained.

When, in the above procedure, the p-nitrophenyl esters of the benzo-hetero acids indicated in Example 4 and the p-nitrophenyl esters of the benzohetero acids indicated in Example 21 are used in place of the l-methylindole- Z-carboxylate, the corresponding 1-acyl-3-indolyl acids are obtained.

EXAMPLE 40 Methyl[1- (Z-mercaptobenzothiazolc-S-carbonyl -2- methyl-S-methxy-3-ind0lyl] ace late The procedures of Example 5A, 5B, 5C, 5D and 5E are followed, using ethyl-Z-mercaptobenzothiazole-5-carboxylate in the procedure of Example 5A and the product thereof successively in 5B, 5C, 5D and SE, to produce methyl[1 (2 mercaptobenzothiazole 5 carbonyl) 2- methyl-5-methoxy-3-indolyl]acetate.

Similarly, when ethyl 1-mercaptobenzothiazole-4-car boxylate, ethyl 2-mercaptobenzooxazole-S-carboxylate, ethyl 2-mercaptobenzooxazole-6-carboxylate are used instead of ethyl-S-chloro-1-mercaptobenzothiazole-3-carboxylate in the above procedure, the corresponding methyl 1 acyl 2 methyl 5 methoxy-3-indolyl acetates are obtained.

EXAMPLE 41 [1(1-methylindole-Z-carbonyl) -5-hydr0xy-4-trifluoromethyl-.i-indolyflacetic acid 0.001 mole of [1 (1 methylindole 2 carbonyl)-5- methoxy-4-trifluoromethyl3-indolyl]acetic acid is added portionwise, with stirring, to 1.5 g. of pyridine hydrochloride at 0 C. On cooling, the residue is dissolved in a small amount of water and extracted with ether to remove starting material. The aqueous solution is adjusted to pH 6.5 and diluted with ethanol to precipitate the zwitter ion 1-methylindole-2-carbonyl-5-hydroxy 4- trifiuoromethyl-3-indolyl acetic acid, which is recrystal lized from aqueous ethanol.

EXAMPLE 42 Propyl [1- benz0tlziaz0le-5-carb0nyl) -4-triflu0r0- methyl-S-indolyl] acetate IA solution of 0.0054 mole of N,N-dicyclohexylcarbodiimide in 60 ml. of anyhdrous tetrahydrofur-an is added to a solution of 0.005 mole of [l-(benzothiazole-S- carbonyl) 4 trifluoromethyl-3-indolyl]acetic acid and 0.0054 mole of n-propyl alcohol in 25 ml. of anhydrous tetrahydrofuran. The reaction mixture is shaken-vigorously and allowed to stand at room temperature overnight. The dicyclohexylurea is filtered 011 and 2 ml. of glacial acetic acid is added to the filtrate. The mixture is allowed to stand for one hour. The solution is filtered and about 200 ml. of ether is added to the filtrate. This tfiltrate is then extracted well with water. The ether solution is dried over sodium sulfate and concentrated in vacuo. The crude material is chromatographed on neutral alumina using ether-petroleum ether (v./v. 2 0- 50%), to obtain propyl(benzothiazole-S-carbonyl)-4- trifluor0methly-3-indolyl acetate.

EXAMPLE 43 2-flu0r0-4-methlyphenylhydrazine 150 ml. of concentrated HCl is slowly added with stirring to 0.1 mole of 2-fluoro-4-methylaniline. When the temperature of this suspension is at --10, 0.1 mole of 40% sodium nitrite solution is added. The above addition is carried out over minutes, maintaining the temperature below 5. A chilled solution of 0.3 mole of stannous chloride in 75 ml. of concentrated hydrochloric acid is then added, dropwise, to this stirred and cooled diazonium solution, over a period of three hours. During this addition the temperature is maintained at 0-5 and after the addition the solution is allowed to remain and 0 for several hours. .The mixture is then filtered and the cake washed with cold sodium chloride solution. This solid is then added to 1 00 ml. of saturated sodium acetate solution, extracted with ether and the ether dried. This crude 2 fluoro-4-methylphenlyhydrazine is finally isolated and purified as its hydrochloride.

When equivalent amounts of 3 fiuoro-4-methylaniline, 2-fiuoro-4-methoxyaniline, 3-fluoro-4-methoxyaniline or 2 fiuoro-4-nitroaniline are used in the above procedure in place of 2-fluoro-4-methylaniline, there is obtained 3- fluoro 4 methylphenlyhydrazine, 2 fluoro 4 methoxyphenylhydrazine or 3-fiuoro-4-methoxyphenylhydrazine, respectively.

EXAMPLE 44 Methyl 4- 0r 6-flu0r0-3-z'nd0lyl acetate 0.07 mole of 3-'fluorophenylhydrazine and 0.08 mole of methly 'y,-, -dimethoxybutyrate are added to 250 ml. of 2 N ethanolic hydrogen chloride and the mixture warmed until reaction sets in. After the initial exothermic reaction stops, the mixture is refluxed for about one-half hour and then concentrated in vacuo to about one-third volume. Four hundred ml. of water are added and the aqueous solution extracted with ether. The other extracts are washed with sodium bicarbonate solution, water, and then dried over sodium sulfate. The ether solution is concentrated to a small volume in vacuo and chromatographed over 200 g. of acid-Washed alumina. The material is eluted with ether-petroleum ether (v./v. 5060%) and distilled in a short path distillation apparatus. Both isomers, namely, methly 4-fluoro-3-indolyl acetate and methly 6-fluoro-3-indolyl acetate are obtained. The structures of these two isomers are differentiated by means of nuclear magnetic resonance spectroscopy.

When an equivalent amount of 3-fiuoro-4-n1ethylphenylhydrazine, 3-fluoro-4-methoxyphenylhydrazine is employed in place of 3 fiuorophenylhydrazine, there is obtained both isomers of each, namely, methyl-(4 fluoro- 5-methyl-3-indolyl)acetate, methyl-(6-fluoro-5-methyl-3- indolyl)acetate; or methyl-(4-fluoro-5-methoXy-3-in d0lyl)acetate; or methyl-( 6 fluoro-5-methoxy-3-indolyl)- acetate, respectively.

Similarly, when an equivalent amount of 2- flu0rophenlyhydrazine, Z-fluoro-4-methylphenylhydrazine or 2-fiuoro-4-methoxyphenylhydrazine is employed in place of 3-fluorophenylhydrazine, there is obtained methyl-(7- fiuoro-3-indolyl acetate, methyl-(7-fluoro-5-methyl-3-indolyl)acetate, or methyl-(7-fluoro-5-methoxy-3-indolyl)- acetate, respectively.

EXAMPLE 45 Methyl a[4- r 6-flu0r0-3-ind0lyl]propionate When the procedure of Example 44 is followed, using methyl wy-dimethoxy-a-methylbutynate in place of methyl 'y,- -dimethoxybutyrate, there is obtained two isomers, namely, methyl u-(4-fluoro-3-indolyl)propionate and methyl ot-(6-fiuoro-3-indolyl) propionate.

When an equivalent amount of .3-flu0ro-4methylphenylhydrazine, 3-fluoro 4-methoxyphenylhydrazine or 4-nitrophenylhydrazine is employed in place of 3-fluorophenylhydrazine, there is obtained both isomers of each, namely, methyl ot-(4-fluoro-5-methyl3-indolyl)propionate, methyl w(6-fiuoro-5-methyl-3-indoly1)propionate or methyl oi-(4-fiuoro-5-methoxy-3-indolyl)propionate, methyl ot-(6-fiuoro-5-methoxy-3-indolyl)propionate, respectively.

Similarly, when an equivalent amount of 2fiuorophenylhydrazine, 2- fluoro-4-me-thylphenylhydrazine or 2- fluoro-4-methoxyphenylhydrazine is employed in place of 3-fiuorophenylhydrazine, there is obtained methyl (M-(7- fiuoro-3-indolyl)propionate, methyl a-(7-fluoro-5-methyl- 3-indolyl)propionate or methyl a-(7-fluoro-5-methoxy-3- indolyl) propionate, respectively.

EXAMPLE 46 Methyl 4- 0r 6-flu0r0-2-mezthyl-3-ind0lyl acetates When the procedure of Example 44 is followed, using methyl levulinate in place of methyl 'y,'y-dimethoxybutyrate, there is obtained two isomers, namely, methyl (4- ifluoro-2-methyl-3-indolyl)acetate and methyl (o-fluorot'Z-methyl-3-indolyl) acetate.

When an equivalent amount of 3-fiuoro-4-methylphenylhydrazine or 3-fluoro-4-methoxyphenylhydrazine is employed in place of 3-fiuorophenyl-hydrazine, there is obtained both isomers of each, namely, methyl(2,5- dimethyl-4-fluoro-3-indolyl)acetate and methyl (2,5- dimethyl-6-fiuoro-3indolyl)acetate, methyl (4-fluoro-5- methoxy-2-methyl-3-indolyl)acetate, methyl (6 fiuoro-5- methoxy-2-methyl-3-inc1olyl)acetate, respectively. Similarly, when an equivalent amount of 2-fluorophenylhydrazine, 2-fiuoro-4-methylphenylhydrazine, or 2-fluor-o-4-methoxyphenylhydrazine is employed in place of 3-fluorophenylhydrazine, there is obtained methyl (7-fluoro 2 -methyl 3 indolyl)acetate, methyl (2,5-dimethyl-7-fluoro-3-indolyl)acetate or methyl (7-fluoro-5- methoxy-2-methyl-3-indolyl)acetate, respectively.

When the procedure of Example 44 is followed, using methyl-wmethyl levulinate in place of methyl-w dimethoxybutyrate, there is obtained two isomers, namely, methyl a-(4-fluoro-2-methyl-3-indolyl)propionate and methyl w 6-fluoro-2-methyl-3-indolyl propionate.

When an equivalent amount of 3-fluoro-4-methylphenylhydrazine or 3-fluoro-4-methylphenylhydrazine is employed in place of 3-fluorophenylhydrazine, there is obtained both isomers of each, namely, methyl ot(2,5- dimethyl-4-fluoro-3-indolyl)propionate, methyl em(2,5- dimethyl-6-fluoro-3-indolyl)propionate, or methyl 00-(4 fiuoro-5-methoxy-2-methyl-3-indolyl)propionate, methyl u-(6-fluoro-5-methoxy 2 methyl-3-indolyl)propionate, respectively.

In addition, when an equivalent amount of Z-fluorophenylhydrazine, 2-fluoro-4-methylphenylhydrazine or 2-fiuoro-4-methylphenylhydrazine is employed in place of 3-fiuorophenylhydrazine, there is obtained methyl ot- (7-fluoro-2-methyl-3-indolyl)propionate, methyl a-(2,5- dimethyl-7-fiuoro-3-indolyl)propionate, or methyl OC (7- fluoro 5 methoxy 2 methyl 3 indolyl)propionate, respectively.

26 EXAMPLE 47 [1-(J-methylindole-Z-carbonyl) -4-flu0r0 6-indolyl] acetic acid A. A solution of 0.05 of a mole of methyl (4-fluoro-3- indolyl)acetate and 0.01 of a mole of sodium in 60 ml. of benzyl alcohol is slowly fractionated over a period of 4 /2 hours through a Vigreux column to remove methanol. The excess benzyl alcohol is then removed by distillation at 60 C. (2.5 mm.) to give a residue of benzyl (4-fiuoro-3-indolyl)acetate.

B. A suspension of 0.046 m. of 50% sodium hydridemineral oil in 250 ml. of dimethylformamide is stirred for 20 minutes under nitrogen with ice-cooling. Then 0.035 m. of the benzyl ester obtained in part A is added and the mixture stirred for 20 minutes. To the above mixture, 0.046 m. of p-nitrophenyl-l-methylindole-Z- carboxylate in 50 ml. of dimethylformamide is added dropwise over a period of 30 minutes. The mixture is stirred in an ice-bath for 5 hours under nitrogen. It is then poured into a mixture of 500 ml. of ether, 5 ml. of acetic acid and 1 l. of iced water. The organic products are extracted with 3 x 300 ml. of ether. The ether solutions are combined and acidified with an ether solution of dry HCl. The ether is decanted and the residue is washed with ether and then mixed with aqueous NaHCO The mixture is extracted with ether and the extracts are dried over sodium sulfate. The solution is then evaporated to near dryness and the residue charged onto a 300 g. neutral alumina column. The crude benzyl [l-(l-methylindole 2 carbonyl) 4 fiuoro-3-indolyl] acetate is eluted with ether-petroleum ether (v./v. 105 0% C. 0.02 of a mole of the ester obtained in part B is added to 50 ml. of ethyl acetate containing a drop of acetic acid and is reduced catalytically at room temperature in the presence of palladium on charcoal catalyst. Upon completion of the reduction, the catalyst is removed by filtration and the filtrate evaporated to yield [l-(l-methylindole 2 carbonyl) 4 -fiuoro 3-indolyl] acetic acid.

EXAMPLE 48 A. (6-meth0xy-3-ind0lyl)acetic anhydride 0.049 mole of dicyclohexylcarbodiimide is dissolved in a solution of 0.10 mole of 6-methoxy-3-indolyl acetic acid in 200 ml. of tetrahydrofuran and allowed to stand at room temperature for 2 hours. The precipitated urea is removed by filtration and the filtrate is evaporated in vacuo to a residue and flushed with Skellysolve B. The residual oily anhydride obtained is used without purifica tion in the next step.

B. (t-Butyl 6-melh0xy-3-indolyl) acetate 25 ml. of t-butyl alcohol and 0.3 g. of fused zinc chlo ride were added to the anhydride from part A. The solution is refluxed for 16 hours and the excess alcohol is removed in vacuo. The residue is then dissolved in either and washed several times with saturated salt solu* tion. The ether extract is dried over magnesium sulfate and the solution treated with charcoal. The ether solu tion is then evaporated and flushed several times with Skellysolve B for complete removal of the alcohol. This residual oily ester is used without purification in the next step.

C. [t-Butyl 1-(1-methylind0le-2-carb0nyl)-6-meth0xy- 3-indolyl1acetate .065 mole of the crude ester, as obtained in step B, is added to 450 ml. of dimethylformamide and cooled to 4 in an ice bath. .098 mole of a 50% suspension of sodium hydride is added portionwise to this stirred solution. After 15 minutes, 0.085 mole of p-nitrophenyl 1-methylindole-Z-carboxylate is added over a 10-minute interval. This mixture is then stirred for 9 hours, with out replenishing the ice bath. At this time, the mixture is poured into one liter of 5% acetic acid and extracted with ether. The ether solution is acidified with an ether solution of dry HCl. The ether is decanted and the residue is washed with ether and then mixed with aqueous NaHCO The mixture is extracted with ether and the ether extract is dried over magnesium sulfate. It is then treated with charcoal and evaporated to a residue. The crude product, thus obtained, is chromatographed on 600 g. of neutral alumina using a mixture of (v./v. 10-50%) ether-petroleum ether as eluent.

D. [1-(1-methylindole-Z-carbonyl) -6-meth0xy-3 indolyl] acetic acid A mixture of 1.16 g. of the ester obtained in step C and 0.1 g. powdered porous plate is heated, with stirring, in an oil bath at 210 C. under nitrogen for 2 hours. The product is isolated in the same manner as Example 6D.

E. [1- (1-methylindole-Z-carbonyl) -7-meth0xy-3- indolyl] acetic acid When the procedure of parts A, B, C and D is used, starting with 7-methoxy-3-indolylacetic acid instead of the 6-methoxy isomer, there is obtained [l-(1methyl indole-Z-carbonyl) -7-methoxy-3-ind0lyl] acetic acid.

EXAMPLE 49 [1-(J-methylindole-Z-carbonyl) -5,7-dimethxy-3- indolyflacetic acid A. 5,T-DIMETHOXYGRAMINE A solution of 0.032 mole of 5,7-dimethoxyindole in 40 ml. of dioxane is added dropwise, over a period of 30 minutes, to an ice-cooled, stirred mixture of 40 ml. of dioxane, 40 ml. of acetic acid, 3.2 ml. of 36% aqueous formaldehyde and 8.8 ml. of 25% aqueous dimethylamine. The clear solution is stirred and cooled for two hours and then allowed to Warm up to room temperaturee overnight. To this solution is added 500 ml. of water. The turbid mixture is then treated with charcoal and filtered through a silicaceous filter aid. The clear filtrate is made alkaline with 400 mil. of dilute sodium hydroxide solution, and placed in a refrigerator, to cool. This mixture is then filtered and the solid gramine is washed with water and dried.

B. 5,7-DIMETHOXY-LNDOLYL-3-A'CET ONITRILE 0.106 mole of the gramine obtained in A is added to 420 ml. of methyliodide, with vigorous stirring, over a period of 20 minutes. The reaction mixture is then allowed to remain at 5 for 15 hours. filtered and the iodine metholate cake is dried at 50. This solid is dissolved in a solution of 60 g. of sodium cyanide in one liter of Water and warmed for two hours at 80. The desired product is extracted with chloroform which is then evaporated to give a crude oily product. The oil is then dissolved in 250 ml. of ether, filtered and the filtrate concentrated. This concentrate is then diluted with petroleum ether, .at which point the 5,7 dimethoxy indolyl-3-acetonitrile precipitates. The mixture is then filtered and the cake dried.

C. 5,7DIMETHOXY-INDOLYL-3-ACETIC ACID 0.08 mole of the nitrile obtained from B is added to a solution of 140 ml. of alcohol, 100 ml. of water and 4.3 g. of potassium hydroxide and refluxed for 15 hours. The mixture is brought to room temperature and 60 ml. of glacial acetic acid is added. The solution is then filtered through a talc filter and the filtrate diluted with 500 ml. of water. The precipitated 5,7-dimethoxyindolyl-3-acetic acid is then filtered and dried.

D. [1-('l-METHYLINDOLE-2-CARBONYL)-5,7-DIMETH- OXY-3-INDOLYL1ACETIC ACID The procedures of Example 48A, 48B, 48C and 48D are followed using the product of part C of this example in place of the 6-methoxy-3-indolylacetic acid, to produce The solution is [l (1 methylindole Z-carbonyl)-5,7-dimethoxy-3-indolyl]acetic acid. When 5,6-dimethoxy-3-indolylace-tic acid is used in place of 6-methoxy-3-indolylacetic acid in the above procedure, there is obtained [l-(l-m'ethylindole-2-carbonyl) -5,6-dimethoxy-3-indolyl] acetic acid.

When 5,6-methylenedioxyindole or 2-methy-l-6-methoxyindole is used in place of 5,7-dimethoxyindole in the procedure of parts A, B and C, there is obtained Z-methyl-6-methoxy-3-indolylacetic acid or 5,6-methylene-dioxy- 3-indolylacetic acid, which, where used in the procedure of part D gives [1 (l methylindole 2-carbonyl)-5,6- methylenedioxy-3-indolyl]acetic acid or [1-( l-methylindole 2 carbonyl)-2-methyl-6-methoxy-3-indolyl]acetic acid.

EXAMPLE 5 0 Methyl 4-benzyloxy-3-indolyl acetate A. l BENZYLOXY-3-INDOLYL ACETONITRILE The procedure of Example 49A and 49B is followed, using 4-benzyloxyindole in place of the 5,7-dimethoxyindole, to give 4-benzyloxy-3-indolyl acetouitrile.

B. METHYL 2-(A-BENZYLOXY-I NDOLYL-S)ACETATE A mixture of 0.1 mole of (4-benzyloxy-indolyl-3-)- acetonitrile in ml. methanol, containing 30 g. dry hydrogen chloride is refluxed for 2 hours. The reaction mixture is taken to dryness and the residue distributed between 10% sodium bicarbonate solution and chloroform. The chloroform layer is dried with anhydrous sodium sulfate and taken to dryness in vacuo. The residue is reasonably pure ester.

Similarly, when 7-benzyloxy-3-indolylacetonitrile is used instead of the 4-isomer, there is obtained methyl 7-benzyloxy-3-indolyl acetate. When S-benzyloxyindole and 6-benzyloxyindole are used in the procedure of part A and B of this example, there are produced methyl 5-benzyloxy-3-indolyl acetate and methyl 6-benzyloxy-3- indolyl acetate.

EXAMPLE 5 1 take ceases. The catalyst is filtered and the filtrate is taken to dryness in vacuo.

B. METHYL 4-METHOXY-3-INDOLYL ACETATE A solution of methyl 4-hydroxy-3-indolyl acetate (10.5

g., 0.065 m.) in 96 ml. 10% sodium hydroxide is stirredv and treated with 7.5 ml. dimethyl sulfate. After stirring for several hours, the crude product is extracted with ether, Washed with water and dried over sodium sulfate. The ether solution is evaporated in vacuo and the residue is chromatographed on 200 g. of acid-washed alumina using a mixture of ether-petroleum ether (v./v. 2550%) as the eluent.

C. 4-METHOXY-3-INDOLYLACETIC ACID A solution of methyl 4-methoxy-3-indolyl acetate in excess 2 N absolute ethanolic potassium hydroxide is allowed to stand overnight, diluted with water and extracted with ether. The aqueous layer is acidified. The precipitate is collected and recrystallized from aqueous ethanol.

D. [l- (l-METHYLINDOLE-Z-CARBONYL) -4-METHOXY-3- INDOLYLJACETIC ACID The procedure of Examples 48A, 48B, 48C and 48D is followed using the product of part C in place of 6 methoxy-3-indo-lylacetic acid, to produce [l-(l-methyl indole-2-carbonyl)-4-methoxy-3-indolyl] acetic acid.

29 EXAMPLE s2 [1 (1-methylindoZe-Z-carbonyl) --chl0ro-6- methoxy-3-indolyl1acetic acid A. 5CHLORO6-METHOXY-3-INDOLYLACTIC ACID When 5-chloro-6-methoxy-3-indolylacetonitrile is used in place of 5,7-dimethoxy-indolyl-3-acetonitrile, in the prcoedure of Example 49C, there is obtained 5-chloro-6- methoxy-B-indolylaoetic acid.

B. [1-(1-METHYLI-NDOLE-2-CARBONYL) -5-CHLORO-6' METHOXY-S-INDOLYL1ACETIC ACID When the procedures of Example 48A, 48B, 48C and 48D are followed, using 5-chloro-6-methoxy-3-indolylacetic acid as the starting material, there is obtained [l-(lmethylindole-Z-carbonyl)-5-chloro-6-methoxy 3 indoly] acetic acid.

C. l1-(1-METHYLI NDOLE-2-CARBONYL)2 METHYL7- l\IETHOXY-3-I-NDOLYL]ACETIC ACID When 2methyl-7-methoxylindole is used in place of 5,7-dimethoxyindole in the procedure of Example 49A,

493 and 49C and the product is used in the procedures of Example 48A, 48B, 48C and 48D, there is obtained [l-(1-methylindole-2-carbonyl)-2-methyl-7 methoxy 3- indolyl]acetic acid.

EXAMPLE 5 3 [1-(1-methylindole-Z-carbonyl) -2-methyl-4-meth0xy- 3-ind0lyl] acetic acid A. Z-METI-IYL-et-METHOXYINDOLE to a solution of ml. of diazomethane in 200 ml. of

ether, with agitation at 0. The reaction mixture is allowed to remain overnight at room temperature. The solvent is then removed under reduced pressure to yield a residue containing the ketone. The 6-methoXy-2-nitrophenyl di-azomethyl ketone is crystallized from this residue using dioxane.

(3) G-methoxy-Z-nitrophenylacetic acid.-A solution of .044 mole of the diazoketone obtained in (2) in 75 ml. of dioxane, is added over a period of 20 minutes to a freshly prepared solution of 4.0 g. of silver oxide, 3.0 g. of sodium thiosulfate and 5.0 g. of sodium carbonate in 150 ml. distilled Water. The temperature of the reaction mixture is maintained at 50-60 during the addition and for an additional hour. At this point, the mixture is brought to a temperature of 90-95 for /2 hour. The mixture is then filtered and the filtrate is diluted with 200 ml. of water, acidified with dilute nitric acid and extracted with chloroform (3 x 200 ml.). The combined chloroform extract is washed with 50 ml. of Water and dried over sodium sulfiate. The chloroform is then removed and the residue extracted with boiling Water (2 x 100 ml.). Concentration of the water solution, followed by cooling, precipitates the 6-methoxy-2-nitrophenyl acetic acid.

(4) Ethyl 6-methoxy-Z-nitrophenylacetyl malolmtc. The product from A(3) is used in the procedure of Part A(l) to give the corresponding acid chloride. A solution of 0.02 mole of this compound in 25 ml. of ether is gradually added to a refluxing ether solution of ethyl ethoxymagnesiomalonate. Heating is continued until stirring is diflicult due to formation of a viscous oil. The cooled mixture is then shaken with dilute H 50 (2.5 g.

in 20 ml. H O) until the oily magnesium complex has dissolved. The ethereal phase is separated, washed with water and dried over Na SO Evaporation yields the crude ethyl 6-methoXy-2-nitrophenylacetylmalonate.

(5) 6-meth0xy-2-nitr0phenylacet0ne.A solution of 5.7 g. of the product from A(4), 12 ml. of acetic acid, 1.5 ml. of sulfuric acid and 8 ml. of water is refluxed for 6 hours. The cool-ed solution is made alkaline with 5 N sodium hydroxide and extracted with ether (3 x 50 ml.). The combined ethereal extract is washed With water, dried over sodium sulfate and evaporated to give an oil which rapidly solidifies. Crystallization of this solid from ethanol yields 6-methoxy-2-nitrophenylacetone.

(6) 4-methoxy-Z-methylindole.-1.2 g. of the product from A(S) is added to a mixture of ml. of ethyl alcohol and 1.0 g. of Raney nickel. This solution is shaken at room temperature and atmospheric pressure, in hydrogen for /2 hour. The solution is then filtered and the filtrate evaporated under reduced pressure. Crystallization from light petroleum ether yields 4-methoxy- 2-methylindole.

B. 2-METHYL-l-METHOXY-3-LNDOLYLACETIC ACID When 4-methoxy-2-methylindole is used in place of 5,7-dimethoxyindole as described in Example 49A, 49B, and 49C, there is obtained 2-methyl-4-m-ethoxy-3-indolyl acetic acid.

C. [1- (l-METI-IYLI'NDOLE-2-CARBONYL) -2-METHYL-4- METHOXYfi-LNDOLYL]ACETIC A'CID When the product from 53B is used in place of 6-methoxy-3-indoly1 acetic acid is described in Example 48A, 48B, 48C and 48D, there is obtained [l-(l-methylindole- 2-carbonyl)-2-rnethyl-4-methoxy-3-indol.yl]acetic acid.

EXAMPLE 54 [1- (1-methylindo le-2-carbo nyl) -7-methoxy-5- methyl-3-ind0lyl1acetic acid A. 7-METHOXY-5-METHYLINDOLE 0.1 mole of 4-methyl-o-anisidine is added to 0.1 mole of monochloroacetaldehyde and the mixture is refluxed for 2 hours. The water formed is distilled off and the residue is heated at 210220 for an additional hour. This residue is then chromatographed on acid-washed alumina and eluted with ether:petroleum ether. The eluent is removed under reduced pressure and 7-methoxy- S-methylindole is obtained.

B. [1-(lMETI-IYLINDOLE-Z-CARBONYL)-7-METHOXY-5- METHYL-3INDOLYL]ACETIC ACID The product from part A is used in the procedures of Example 48A, 48B, 48C, and 48D. There is obtained [11 (1 methylindole 2-carbonyl)-7-methoxy-5-methyl- 3-indoly1] acetic acid.

C. [1-(1-METHYLINDOLE-2-CARBONYL)-5-FLUORO7- METHOXYe-INDOLYLJACETI C ACID The procedures of parts A and B are followed star-ting with 4-fluoro-o-anisidine, to give [l-(l-methylindole-Z- carbonyl)-5fiuoro-71methoxy-3 indolyllacetic acid.

D. [1-(11\L[ETHYLINDOLE-2-CARBONYL)-5-INITRO-7- METHOXY-3-INDOLYL]ACETIC A'CID The procedures of parts A and B are followed starting with 4-nitro-o-anisidine, to give [l-(l-methylindole-Q- carbonyl) 5 nitro 7 methoxy-3-indolyl1acetic acid. When this is used in the procedure of Example 16, there is produced [Id-methylindole 2 carbonyl) 5 dimethylamino-7-mezthxy-3-indolyl]acetic acid.

EXAMPLE 55 [1-(1-methylindole-Zwarbonyl)-2-allyl-5-meth0xy- 3-ind0lyl1acetic acid A. fi-METHOXY-Z-INDOLYL ACETALDEHYDE A solution of S-meth-oxy-Z-indolylacetyl chloride (0.1 mole) in dry tetrahydrofuran is treated with 0.25 mole of lithium aluminum tri-t-butoxy hydride with ice-cooling and stirring. After the intial reaction, the mixture is stirred at room temperature for four hours and poured into ice. Excess of acetic acid is added and the product is extracted with ether. The ethereal solution is washed with sodium bicarbonate, dried over sodium sulfate and evaporated to a syrup. Chromatography of the residue on a column of silica gel, using ether-petroleum ether (v./v. l-30%) .as eluent, gives methoxy-2-indolyl aoetaldehyde.

B. 2-ALLYL-5-METHOXYI-NDOLE A solution of 0.1 mole of the aldehyde and 0.12 mole of methylene triphenylphosphine, prepared in situa from 0.12 mole of methyl triphenylphosphonium iodide and 0.12 mole of n-butyl lithium, in benzene is stirred at room temperature for four hours and then at 80 for one hour. The solution is washed with 0.5 N hydrochloric acid, water and dried over sodium sulfate. Evaporation of the solvent in vacuo and chromatography of the residue on a column of 300 g. acid-washed alumina, using ether-petroleum ether (v./v. 020%) as eluent, gives 2-allyl-5 methoxyindole.

C. 2-ALLYL-5-METHOXYGRAMINE A solution of 0.032 mole of 2-allyl-5-methoxyindole in 40 ml. of dioxane is added dropwise, over 30 minutes, to an ice-cooled stirred mixture of 40 ml. di-oxane, 40 ml. acetic acid, 3.2 ml. 36% aqueous formaldehyde and 8.8 ml. 25% aqueous dimethylamine. The clear solution is stirred and cooled for two hours and then allowed to warm to room temperature overnight. To this solution is added 500 ml. of water. The turbid mixture is then treated with charcoal and filtered through a silicaceous rfilter aid. The clear filtrate is made alkaline with 400 ml. of dilute N aOH solution and cooled in a refrigerator. The mixture is filtered and the solid gramine is washed with water and dried.

D. 2-ALLYL-5-METHOXY-3-INDOLYL ACETONITRILE 0.106 mole of the .gramine from part C is added to 420 ml. of methyliodide, with vigorous stirring, over a period of 20 minutes. The reaction mixture is then allowed to remain at 5 for 15 hours. The solution is filtered and the iodine metholate cake is dried at 50 C. The solid is dissolved in a solution of 60 g. of NaCN in one liter and warmed for 2 hours at 80 The desired product is extracted with chloroform which is then evaporated to give a crude oily product. The oil is then dissolved in 250 ml. of ether, filtered and the filtrate is concentrated. The concentrate is diluted with petroleum ether, at which point the 2-allyl-5-methoxy-3-indoly aceton-itrile precipitates. The mixture is filtered and the cake dried.

E. 2-ALLYL-5-METHOXY-3-INDOLYLACETIC ACID 0.08 mole of 2-allyl-5-methoxy-3-iudolyl acetonitrile is added to a mixture of 140 ml. of alcohol, 100 ml. of Water and 4.3 g. of KOH. The mixture is refluxed 15 hours and then brought to room temperature. Glacial acetic acid (60 ml.) is added and the solution is filtered through a tale filter. The filtrate is diluted with 500 ml. of water and the precipitated 2-allyl-5-methoxy-3-indolyl acetic acid is separated by filtration and dried.

F. [1-(1-METHYLDNDOLE-2-CARBONYL)-2-ALLYL-5- METHOXY-S-INDOLYL]ACElIC ACID The procedure of Example 48A, B, C, D, and E is followed using the product of part B in place of the 6- methoxy-3-ind-olylacetic acid, to produce [l-(l-methy1- indgle-Z-carbonyl) 2-allyl-5-methoxy 3 indolyllacetic acr EXAMPLE 56 [1 (S-aminobenzisoxazole-Z-carbonyl)-2-me thyl-5- methoxy-3-i1zd0lyl]acetic acid The procedure of Example 12 is followed, using [-(5- nitrobenzisoxazole 2 carbonyl)-2-methyl-5-methoxy-3- 32 indolyl] acetic acid (prepared in Example 8) in place of me-thyl(2 methyl 5-nitro-3-indolyl)acetate, to produce [1 (5 aminobenzisoxaz-ole 2 carbonyl)-2-methyl5- methoxy-S-indolyl]acetic acid.

When the procedure of Example 16 is followed, (omitting the final bicarbonate wash) using the [1-(5-nitrobenzisoxazole-Z-carbonyl) compound from Example 9 in place of the methyl-(1-methy-lindole-2-carbonyl) 2- methyl-5'-nitro-3-indoly-l] aceate used therein, there is obtained [1- S-dimethylaminobenzisoxazole-Z-earbonyl -2- methyl-5-methoxy-3-indolyl] acetic acid.

When the procedure of Example 16 is followed, (omitting the final bicarbonate wash) using the 1-(5-'nitrobenzisoxazole-Z-carbonyl) compound from Example 8 in place of the S-nitro indolyl ester used therein, there is ob [1 (5 acetamidobenzisoxazole 2 carbonyl) 2 methyl-5-methoxy-3-indolyl] acetic acid.

Similarly, when the (prepared in Example 8) are used instead of (S-nitrobenzisoxazole 2-carbonyl) -2-methyl-5-methoxy-3-indolylacetic acid in the above procedure, the corresponding (aminoacyl)-3-indolylaceti-c acid, (1-dimethylaminoacyl)- 3-indolylacetic acid and (l-acetamidoacyl)-3-indolylacetic acid are obtained, respectively.

I claim: 1. A compound of the formula:

l a R5- Horr-o OM \N/R2 7 R4 I in which R is selected from the group consisting of benzisoxazole, benzimidazole, benzofuran, benzothiazole, benzotriazole, benzoxazole, benzothiophene, indole, indazole and an isindazole radical and a substituted benzisoxazole, benzimidazole, benzofuran, benzothiazole, benzotriazole, benzoxazole, benzothiophene, indole, indazole and an isindazole radical in which said substituent is selected from the group consisting of halogen, lower alkyl, lower alkylthio, lower alkoxy, lower alkanoyl, cyano, carb-lower alkoxy, benzylthio, mercapto, nitro, amino, di(lower alkyl)amino, lower alkanoylamino, hydroxy, benzyloxy, di(lower alkanoyl) amino, benzamido, benzenesulfonamido, phenyl, lower alkoxyphenyl, benzoyl, naphthoyl, di(lower alkoxy)phenyl, di(lower alkyl)amino, lower alkyl, amino lower alkyl, lower alkyl amino, nitrophenyl, lower alkanoylamino, phenyl, dihydroxybenzoyl, thenoyl, benzyl, di(lower alkoxy) lower alkyl, lower alkoxy lower alkyl, phenylamino lower alkyl, morpholino lower alkyl, lower alkenyl, halogenobenzyloxy, and lower alkyl benzyloxy;

R is selected from the group consisting of hydrogen,

lower alkenyl and lower alkyl;

R is selected from the group consisting of hydrogen and lower alkyl;

R; is selected from the group consisting of hydrogen,

lower alkyl, lower alkoxy, fluorine and trifiuorom t y R is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, di(lower alky1)amino, lower alkanoylamino, lower alkanoyl, lower alkylamino, blist'hydroxy lower alkyl)amino, l-py rrolidino, 4- methyl-l-piperazinyl, 4-morpholinyl, cyano, amino lower alkyl, di(lower a lkyl)amino, lower alkyl, trifluoromethyl, halogen, di(lower alkyl)sulfamyl, ben- Zylthio, lower alkylbenzylthio, lower alkoxybenzylthio, halogenobenzylthio, benzyloxy, lower alkylbenzyloxy, lower alkoxybenzyloxy, halogenobenzyloxy, lower alkenyl, lower alkenyloxy, l-azacyclopropyl, cyclopropyl(lower alkoxy)methyloxy, and cyclobutyl(lower alkoxy) methyloxy; and

M is selected from the group consisting of OH, NH benzyloxy, lower alkoxy, OZ where Z is selected from the group consisting of alkaline metal, alkaline earth metal, aluminum and magnesium and OY where Y represents the structure:

2. A compound of claim 1 in which R is a lower alkyl substituted benzothiazole radical, R is methyl, R is hydrogen, R is hydrogen, R is methoxy and M is hydroxy.

3. A compound of claim 1 in which R is a lower alkyl substituted benzothiazole radical, R is methyl, R is methyl, R is hydrogen, R is methoxy and M is hydroxy.

4. A compound of claim 1 in which R is a lower alkyl substituted benzothiazole radical, R is methyl, R is hydrogen, R is hydrogen, R is dimethylamino and M is hydroxy.

5. A compound of claim 1 in which R is a lower alkyl substituted benzothiazole radical, R is methyl, R is hydrogen, R is hydrogen, R is fluoro and M is hydroxy.

6. A compound of claim 1 in which R is a halo substituted benzothiazole radical, R is methyl, R is hydrogen, R is hydrogen, R is methoxy and M is hydroxy.

7. A compound of claim 1 in which R is a halo substituted benzothiazole radical, R is methyl, R is methyl, R is hydrogen, R is methoxy and M is hydroxy.

8. A compound of claim 1 in which R is a halo substituted benzothiazole radical, R is methyl, R is hydrogen,

R is hydrogen, R is dimethylamino and M is hydroxy. 5

9. A compound of claim 1 in which R is a halo substituted benzothiazole radical, R is methyl, R is hydrogen, R is hydrogen, R is fluoro and M is hydroxy.

10. A compound of claim 1 in which R is a lower alkyl substituted benzofuran radical, R is methyl, R is hydrogen, R is hydrogen, R is methoxy and M is hydroxy.

11. A compound of claim 1 in which R is a lower alkyl substituted benzofuran radical, R is methyl, R is methyl, R is hydrogen, R is methoxy and M is hydroxy.

12. A compound of claim 1 in which R is a lower alkyl substituted benzofuran radical, R is methyl, R is hydrogen, R is hydrogen, R is dimethylamino and M is hydroxy.

13. A compound of claim 1 in which R is a lower alkyl substituted benzofuran radical, R is methyl, R is hydrogen, R is hydrogen, R is fluoro and M is hydroxy.

14. A compound of claim 1 in which R is a lower alkyl substituted benzoxazole radical, R is methyl, R is hydrogen, R is hydrogen, R is methoxy and M is hydroxy.

15. A compound of claim 1 in which R is a lower alkyl substituted benzoxazrole radical, R is methyl, R is methyl, R is hydrogen, R is methoxy and M is hydroxy.

16. A compound of claim 1 in which R is a lower alkyl substituted benzoxazole radical, R is methyl, R is hydrogen, R is hydrogen, R is dimethylamino and M is hydroxy.

17. A compound of claim 1 in which R is a lower alkyl substituted benzoxazole radical, R is methyl, R is hydrogen, R is hydrogen, R is :fluoro and M is hydroxy.

18. A compound of claim 1 in which R is a halo substituted thionaphthene radical, R is methyl, R is hydrogen, R is hydrogen, R is methoxy and M is hydroxy.

19. A compound of claim 1 in which R is a halo substituted thionaphthene radical, R is methyl, R is methyl, R is hydrogen, R is methoxy and M is hydroxy.

20. A compound of claim 1 in which R is a halo substituted thionaphthene radical, R is methyl, R is hydrogen, R is hydrogen, R is dimethylamino and M is hydroxy.

No references cited.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

0 RICHARD J. GALLAGHER, Assistant Examiner. 

